Antibodies to IL-6 and use thereof

ABSTRACT

The present invention is directed to antibodies and fragments thereof and humanized versions thereof having binding specificity for IL-6. Another embodiment of this invention relates to the antibodies described herein, and binding fragments thereof, comprising the sequences of the V H , V L  and CDR polypeptides described herein, and the polynucleotides encoding them. The invention also contemplates conjugates of anti-IL-6 antibodies and binding fragments thereof conjugated to one or more functional or detectable moieties. The invention also contemplates methods of making said anti-IL-6 antibodies and binding fragments thereof. Embodiments of the invention also pertain to the use of anti-IL-6 antibodies, and binding fragments thereof, for the diagnosis, assessment and treatment of diseases and disorders associated with IL-6. These antibodies may bind at least one of soluble IL-6, cell surface expressed IL-6, IL-6/IL-6R and/or prevent the association of IL-6 and IL-6R, the association of IL-6/IL-6R and gp130 and or the formation of IL-6/IL-6R/gp130 multimers and thereby inhibit a biological effect associated with any of the foregoing.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Ser. No. 13/277,390, filedOct. 20, 2011, which is a divisional of U.S. Ser. No. 12/391,717, filedFeb. 24, 2009, (now U.S. Pat. No. 8,178,101, issued May 15, 2012), whichis a continuation-in-part of U.S. Ser. No. 12/323,066 filed Nov. 25,2008 (now U.S. Pat. No. 8,404,235, issued Mar. 26, 2013), which is acontinuation-in-part of U.S. Ser. No. 12/153,612 filed May 21, 2008 (nowU.S. Pat. No. 7,935,340, issued May 3, 2011), which claims the benefitof U.S. Ser. No. 60/924,550 filed May 21, 2007, and is acontinuation-in-part of U.S. Ser. No. 12/153,611 filed May 21, 2008,which claims the benefit of U.S. Ser. No. 60/924,551 filed May 21, 2007,and is a continuation-in-part of U.S. Ser. No. 12/124,723 filed May 21,2008;

U.S. Ser. No. 12/391,717 is also a continuation-in-part of U.S. Ser. No.12/323,147 filed Nov. 25, 2008 (now U.S. Pat. No. 7,906,117, issued Mar.15, 2011), which is a continuation-in-part of U.S. Ser. No. 12/153,612filed May 21, 2008 (now U.S. Pat. No. 7,935,340, issued May 3, 2011),which claims the benefit of U.S. Ser. No. 60/924,550 filed May 21, 2007,and is a continuation-in-part of U.S. Ser. No. 12/153,611 filed May 21,2008, which claims the benefit of U.S. Ser. No. 60/924,551 filed May 21,2007, and is a continuation-in-part of U.S. Ser. No. 12/124,723 filedMay 21, 2008;

U.S. Ser. No. 12/391,717 is also a continuation-in-part of U.S. Ser. No.12/323,194 filed Nov. 25, 2008 (now U.S. Pat. No. 8,252,286, issued Aug.28, 2012), which is a continuation-in-part of U.S. Ser. No. 12/153,612filed May 21, 2008 (now U.S. Pat. No. 7,935,340, issued May 3, 2011),which claims the benefit of U.S. Ser. No. 60/924,550 filed May 21, 2007,and is a continuation-in-part of U.S. Ser. No. 12/153,611 filed May 21,2008, which claims the benefit of U.S. Ser. No. 60/924,551 filed May 21,2007, and is a continuation-in-part of U.S. Ser. No. 12/124,723 filedMay 21, 2008;

U.S. Ser. No. 12/391,717 is also a continuation-in-part of U.S. Ser. No.12/366,567 filed Feb. 5, 2009 (now U.S. Pat. No. 8,062,864, issued Nov.22, 2011), which is a continuation-in-part of U.S. Ser. No. 12/323,066filed Nov. 25, 2008 (now U.S. Pat. No. 8,404,235, issued Mar. 26, 2013),which is a continuation-in-part of U.S. Ser. No. 12/153,612 filed May21, 2008 (now U.S. Pat. No. 7,935,340, issued May 3, 2011), which claimsthe benefit of U.S. Ser. No. 60/924,550 filed May 21, 2007, and is acontinuation-in-part of U.S. Ser. No. 12/153,611 filed May 21, 2008,which claims the benefit of U.S. Ser. No. 60/924,551 filed May 21, 2007,and is a continuation-in-part of U.S. Ser. No. 12/124,723 filed May 21,2008; and is a continuation-in-part of U.S. Ser. No. 12/323,147 filedNov. 25, 2008 (now U.S. Pat. No. 7,906,117, issued Mar. 15, 2011), whichis a continuation-in-part of U.S. Ser. No. 12/153,612 filed May 21, 2008(now U.S. Pat. No. 7,935,340, issued May 3, 2011), which claims thebenefit of U.S. Ser. No. 60/924,550 filed May 21, 2007, and is acontinuation-in-part of U.S. Ser. No. 12/153,611 filed May 21, 2008,which claims the benefit of U.S. Ser. No. 60/924,551 filed May 21, 2007,and is a continuation-in-part of U.S. Ser. No. 12/124,723 filed May 21,2008; and is a continuation-in-part of U.S. Ser. No. 12/323,194 filedNov. 25, 2008 (now U.S. Pat. No. 8,252,286, issued Aug. 28, 2012), whichis a continuation-in-part of U.S. Ser. No. 12/153,612 filed May 21, 2008(now U.S. Pat. No. 7,935,340, issued May 3, 2011), which claims thebenefit of U.S. Ser. No. 60/924,550 filed May 21, 2007, and is acontinuation-in-part of U.S. Ser. No. 12/153,611 filed May 21, 2008,which claims the benefit of U.S. Ser. No. 60/924,551 filed May 21, 2007,and is a continuation-in-part of U.S. Ser. No. 12/124,723 filed May 21,2008;

the disclosure of each of the foregoing applications is herebyincorporated by reference in its entirety.

SEQUENCE LISTING

The sequence listing in the file named “43272o1503.txt” having a size of315,009 bytes that was created Apr. 30, 2015 is hereby incorporated byreference in its entirety.

BACKGROUND OF THE INVENTION

Field of the Invention

This invention pertains to antibodies and fragments thereof especiallyhumanized versions thereof having binding specificity to IL-6. Theinvention also pertains to methods of screening for diseases anddisorders associated with IL-6, and methods of preventing or treatingdiseases or disorders associated with IL-6 by administering saidantibodies or fragments thereof.

Description of Related Art

Interleukin-6 (hereinafter “IL-6”) (also known as interferon-β₂; B-celldifferentiation factor; B-cell stimulatory factor-2; hepatocytestimulatory factor; hybridoma growth factor; and plasmacytoma growthfactor) is a multifunctional cytokine involved in numerous biologicalprocesses such as the regulation of the acute inflammatory response, themodulation of specific immune responses including B- and T-celldifferentiation, bone metabolism, thrombopoiesis, epidermalproliferation, menses, neuronal cell differentiation, neuroprotection,aging, cancer, and the inflammatory reaction occurring in Alzheimer'sdisease. See A. Papassotiropoulos, et al, Neurobiology of Aging,22:863-871 (2001).

IL-6 is a member of a family of cytokines that promote cellularresponses through a receptor complex consisting of at least one subunitof the signal-transducing glycoprotein gp130 and the IL-6 receptor(“IL-6R”)(also known as gp80). The IL-6R may also be present in asoluble form (“sIL-6R”). IL-6 binds to IL-6R, which then dimerizes thesignal-transducing receptor gp130. See Jones, S A, J. Immunology,175:3463-3468 (2005).

In humans, the gene encoding for IL-6 is organized in five exons andfour introns, and maps to the short arm of chromosome 7 at 7p21.Translation of IL-6 RNA and post-translational processing result in theformation of a 21 to 28 kDa protein with 184 amino acids in its matureform. See A. Papassotiropoulos, et al, Neurobiology of Aging, 22:863-871(2001).

As set forth in greater detail below, IL-6 is believed to play a role inthe development of a multitude of diseases and disorders, including butnot limited to fatigue, cachexia, autoimmune diseases, diseases of theskeletal system, cancer, heart disease, obesity, diabetes, asthma,alzheimer's disease and multiple sclerosis. Due to the perceivedinvolvement of IL-6 in a wide range of diseases and disorders, thereremains a need in the art for compositions and methods useful forpreventing or treating diseases associated with IL-6, as well as methodsof screening to identify patients having diseases or disordersassociated with IL-6. Particularly preferred anti-IL-6 compositions arethose having minimal or minimizing adverse reactions when administeredto the patient. Compositions or methods that reduce or inhibit diseasesor disorders associated with IL-6 are beneficial to the patient in needthereof.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed to specific antibodies and fragmentsthereof especially humanized version thereof having binding specificityfor IL-6, in particular antibodies having specific epitopic specificityand/or functional properties. One embodiment of the inventionencompasses specific humanized antibodies and fragments thereof capableof binding to IL-6 and/or the IL-6/IL-6R complex. These antibodies maybind soluble IL-6 or cell surface expressed IL-6. Also, these antibodiesmay inhibit the formation or the biological effects of one or more ofIL-6, IL-6/IL-6R complexes, IL-6/IL-6R/gp130 complexes and/or multimersof IL-6/IL-6R/gp130.

Another embodiment of this invention relates to the antibodies describedherein, comprising the sequences of the V_(H), V_(L) and CDRpolypeptides described herein, and the polynucleotides encoding them. Inmore specific embodiments of the invention these antibodies will blockgp130 activation and/or possess binding affinities (Kds) less than 50picomolar and/or K_(off) values less than or equal to 10⁻⁴ S⁻¹.

In another embodiment of the invention these antibodies and humanizedversions will be derived from rabbit immune cells (B lymphocytes) andmay be selected based on their homology (sequence identity) to humangerm line sequences. These antibodies may require minimal or no sequencemodifications, thereby facilitating retention of functional propertiesafter humanization.

In another embodiment of the invention the subject antibodies may beselected based on their activity in functional assays such as IL-6driven T1165 proliferation assays, IL-6 simulated HepG2 haptoglobinproduction assays, and the like. A further embodiment of the inventionis directed to fragments from anti-IL-6 antibodies encompassing V_(H),V_(L) and CDR polypeptides, e.g., derived from rabbit immune cells andthe polynucleotides encoding the same, as well as the use of theseantibody fragments and the polynucleotides encoding them in the creationof novel antibodies and polypeptide compositions capable of recognizingIL-6 and/or IL-6/IL-6R complexes or IL-6/IL-6R/gp130 complexes and/ormultimers thereof.

The invention also contemplates conjugates of anti-IL-6 antibodies andbinding fragments thereof conjugated to one or more functional ordetectable moieties. The invention also contemplates methods of makingsaid humanized anti-IL-6 or anti-IL-6/IL-6R complex antibodies andbinding fragments thereof. In one embodiment, binding fragments include,but are not limited to, Fab, Fab′, F(ab′)₂, Fv and scFv fragments.

Embodiments of the invention pertain to the use of anti-IL-6 antibodiesfor the diagnosis, assessment and treatment of diseases and disordersassociated with IL-6 or aberrant expression thereof. The invention alsocontemplates the use of fragments of anti-IL-6 antibodies for thediagnosis, assessment and treatment of diseases and disorders associatedwith IL-6 or aberrant expression thereof. Preferred usages of thesubject antibodies are the treatment and prevention of cancer associatedfatigue, and/or cachexia and rheumatoid arthritis.

Other embodiments of the invention relate to the production of anti-IL-6antibodies in recombinant host cells, preferably diploid yeast such asdiploid Pichia and other yeast strains.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

FIG. 1 shows that a variety of unique epitopes were recognized by thecollection of anti-IL-6 antibodies prepared by the antibody selectionprotocol. Epitope variability was confirmed by antibody-IL-6 bindingcompetition studies (ForteBio Octet).

FIG. 2 shows alignments of variable light and variable heavy sequencesbetween a rabbit antibody variable light and variable heavy sequencesand homologous human sequences and the final humanized sequences.Framework regions are identified FR1-FR4. Complementarity determiningregions are identified as CDR1-CDR3. Amino acid residues are numbered asshown. The initial rabbit sequences are called RbtVL and RbtVH for thevariable light and variable heavy sequences respectively. Three of themost similar human germline antibody sequences, spanning from Framework1 through to the end of Framework 3, are aligned below the rabbitsequences. The human sequence that is considered the most similar to therabbit sequence is shown first. In this example those most similarsequences are L12A for the light chain and 3-64-04 for the heavy chain.Human CDR3 sequences are not shown. The closest human Framework 4sequence is aligned below the rabbit Framework 4 sequence. The verticaldashes indicate a residue where the rabbit residue is identical with oneor more of the human residues at the same position. The bold residuesindicate that the human residue at that position is identical to therabbit residue at the same position. The final humanized sequences arecalled VLh and VHh for the variable light and variable heavy sequencesrespectively. The underlined residues indicate that the residue is thesame as the rabbit residue at that position but different than the humanresidues at that position in the three aligned human sequences.

FIG. 3 demonstrates the high correlation between the IgG produced andantigen specificity for an exemplary IL-6 protocol. 9 of 11 wells showedspecific IgG correlation with antigen recognition.

FIG. 4 provides the α-2-macroglobulin (A2M) dose response curve forantibody Ab1 administered intravenously at different doses one hourafter a 100 μg/kg s.c. dose of human IL-6.

FIG. 5 provides survival data for the antibody Ab1 progression groupsversus control groups.

FIG. 6 provides additional survival data for the antibody Ab1 regressiongroups versus control groups.

FIG. 7 provides survival data for polyclonal human IgG at 10 mg/kg i.v.every three days (270-320 mg tumor size) versus antibody Ab1 at 10 mg/kgi.v. every three days (270-320 mg tumor size).

FIG. 8 provides survival data for polyclonal human IgG at 10 mg/kg i.v.every three days (400-527 mg tumor size) versus antibody Ab1 at 10 mg/kgi.v. every three days (400-527 mg tumor size).

FIG. 9 provides a pharmacokinetic profile of antibody Ab1. Plasma levelsof antibody Ab1 were quantitated through antigen capture ELISA. Thisprotein displays a half life of between 12 and 17 days consistent withother full length humanized antibodies.

FIGS. 10 A-D provide binding data for antibodies Ab4, Ab3, Ab8 and Ab2,respectively. FIG. 10 E provides binding data for antibodies Ab1, Ab6and Ab7.

FIG. 11 summarizes the binding data of FIGS. 10 A-E in tabular form.

FIG. 12 presents the sequences of the 15 amino acid peptides used in thepeptide mapping experiment of Example 14.

FIG. 13 presents the results of the blots prepared in Example 14.

FIG. 14 presents the results of the blots prepared in Example 14.

FIG. 15 depicts preferred humanized heavy and light chain regionsderived from Ab1. These sequences are contained in SEQ ID NOs: 647-657.

FIG. 16 depicts preferred humanized heavy and light chain regionsderived from Ab1. These sequences are contained in SEQ ID NOs: 647-650,652-657, and 709.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS Definitions

It is to be understood that this invention is not limited to theparticular methodology, protocols, cell lines, animal species or genera,and reagents described, as such may vary. It is also to be understoodthat the terminology used herein is for the purpose of describingparticular embodiments only, and is not intended to limit the scope ofthe present invention which will be limited only by the appended claims.

As used herein the singular forms “a”, “and”, and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, reference to “a cell” includes a plurality of such cells andreference to “the protein” includes reference to one or more proteinsand equivalents thereof known to those skilled in the art, and so forth.All technical and scientific terms used herein have the same meaning ascommonly understood to one of ordinary skill in the art to which thisinvention belongs unless clearly indicated otherwise.

Interleukin-6 (IL-6): As used herein, interleukin-6 (IL-6) encompassesnot only the following 212 amino acid sequence available as GenBankProtein Accession No. NP_000591:

(SEQ ID NO: 1) MNSFSTSAFGPVAFSLGLLLVLPAAFPAPVPPGEDSKDVAAPHRQPLTSSERIDKQIRYILDGISALRKETCNKSNMCESSKEALAENNLNLPKMAEKDGCFQSGFNEETCLVKIITGLLEFEVYLEYLQNRFESSEEQARAVQMSTKVLIQFLQKKAKNLDAITTPDPTTNASLLTKLQAQNQWLQDMTTHLILRSFKE FLQSSLRALRQM,but also any pre-pro, pro- and mature forms of this IL-6 amino acidsequence, as well as mutants and variants including allelic variants ofthis sequence.

Mating competent yeast species: In the present invention this isintended to broadly encompass any diploid or tetraploid yeast which canbe grown in culture. Such species of yeast may exist in a haploid,diploid, or tetraploid form. The cells of a given ploidy may, underappropriate conditions, proliferate for indefinite number of generationsin that form. Diploid cells can also sporulate to form haploid cells.Sequential mating can result in tetraploid strains through furthermating or fusion of diploid strains. In the present invention thediploid or polyploidal yeast cells are preferably produced by mating orspheroplast fusion.

In one embodiment of the invention, the mating competent yeast is amember of the Saccharomycetaceae family, which includes the generaArxiozyma; Ascobotryozyma; Citeromyces; Debaryomyces; Dekkera;Eremothecium; Issatchenkia; Kazachstania; Kluyveromyces; Kodamaea;Lodderomyces; Pachysolen; Pichia; Saccharomyces; Saturnispora;Tetrapisispora; Torulaspora; Williopsis; and Zygosaccharomyces. Othertypes of yeast potentially useful in the invention include Yarrowia,Rhodosporidium, Candida, Hansenula, Filobasium, Filobasidellla,Sporidiobolus, Bullera, Leucosporidium and Filobasidella.

In a preferred embodiment of the invention, the mating competent yeastis a member of the genus Pichia. In a further preferred embodiment ofthe invention, the mating competent yeast of the genus Pichia is one ofthe following species: Pichia pastoris, Pichia methanolica, andHansenula polymorpha (Pichia angusta). In a particularly preferredembodiment of the invention, the mating competent yeast of the genusPichia is the species Pichia pastoris.

Haploid Yeast Cell: A cell having a single copy of each gene of itsnormal genomic (chromosomal) complement.

Polyploid Yeast Cell: A cell having more than one copy of its normalgenomic (chromosomal) complement.

Diploid Yeast Cell: A cell having two copies (alleles) of essentiallyevery gene of its normal genomic complement, typically formed by theprocess of fusion (mating) of two haploid cells.

Tetraploid Yeast Cell: A cell having four copies (alleles) ofessentially every gene of its normal genomic complement, typicallyformed by the process of fusion (mating) of two haploid cells.Tetraploids may carry two, three, four, or more different expressioncassettes. Such tetraploids might be obtained in S. cerevisiae byselective mating homozygotic heterothallic a/a and alpha/alpha diploidsand in Pichia by sequential mating of haploids to obtain auxotrophicdiploids. For example, a [met his] haploid can be mated with [ade his]haploid to obtain diploid [his]; and a [met arg] haploid can be matedwith [ade arg] haploid to obtain diploid [arg]; then the diploid[his]×diploid [arg] to obtain a tetraploid prototroph. It will beunderstood by those of skill in the art that reference to the benefitsand uses of diploid cells may also apply to tetraploid cells.

Yeast Mating: The process by which two haploid yeast cells naturallyfuse to form one diploid yeast cell.

Meiosis: The process by which a diploid yeast cell undergoes reductivedivision to form four haploid spore products. Each spore may thengerminate and form a haploid vegetatively growing cell line.

Selectable Marker: A selectable marker is a gene or gene fragment thatconfers a growth phenotype (physical growth characteristic) on a cellreceiving that gene as, for example through a transformation event. Theselectable marker allows that cell to survive and grow in a selectivegrowth medium under conditions in which cells that do not receive thatselectable marker gene cannot grow. Selectable marker genes generallyfall into several types, including positive selectable marker genes suchas a gene that confers on a cell resistance to an antibiotic or otherdrug, temperature when two ts mutants are crossed or a ts mutant istransformed; negative selectable marker genes such as a biosyntheticgene that confers on a cell the ability to grow in a medium without aspecific nutrient needed by all cells that do not have that biosyntheticgene, or a mutagenized biosynthetic gene that confers on a cellinability to grow by cells that do not have the wild type gene; and thelike. Suitable markers include but are not limited to: ZEO; G418; LYS3;MET1; MET3a; ADE1; ADE3; URA3; and the like.

Expression Vector: These DNA vectors contain elements that facilitatemanipulation for the expression of a foreign protein within the targethost cell. Conveniently, manipulation of sequences and production of DNAfor transformation is first performed in a bacterial host, e.g. E. coli,and usually vectors will include sequences to facilitate suchmanipulations, including a bacterial origin of replication andappropriate bacterial selection marker. Selection markers encodeproteins necessary for the survival or growth of transformed host cellsgrown in a selective culture medium. Host cells not transformed with thevector containing the selection gene will not survive in the culturemedium. Typical selection genes encode proteins that (a) conferresistance to antibiotics or other toxins, (b) complement auxotrophicdeficiencies, or (c) supply critical nutrients not available fromcomplex media. Exemplary vectors and methods for transformation of yeastare described, for example, in Burke, D., Dawson, D., & Stearns, T.(2000). Methods in yeast genetics: a Cold Spring Harbor Laboratorycourse manual. Plainview, N.Y.: Cold Spring Harbor Laboratory Press.

Expression vectors for use in the methods of the invention will furtherinclude yeast specific sequences, including a selectable auxotrophic ordrug marker for identifying transformed yeast strains. A drug marker mayfurther be used to amplify copy number of the vector in a yeast hostcell.

The polypeptide coding sequence of interest is operably linked totranscriptional and translational regulatory sequences that provide forexpression of the polypeptide in yeast cells. These vector componentsmay include, but are not limited to, one or more of the following: anenhancer element, a promoter, and a transcription termination sequence.Sequences for the secretion of the polypeptide may also be included,e.g. a signal sequence, and the like. A yeast origin of replication isoptional, as expression vectors are often integrated into the yeastgenome.

In one embodiment of the invention, the polypeptide of interest isoperably linked, or fused, to sequences providing for optimizedsecretion of the polypeptide from yeast diploid cells.

Nucleic acids are “operably linked” when placed into a functionalrelationship with another nucleic acid sequence. For example, DNA for asignal sequence is operably linked to DNA for a polypeptide if it isexpressed as a preprotein that participates in the secretion of thepolypeptide; a promoter or enhancer is operably linked to a codingsequence if it affects the transcription of the sequence. Generally,“operably linked” means that the DNA sequences being linked arecontiguous, and, in the case of a secretory leader, contiguous and inreading frame. However, enhancers do not have to be contiguous. Linkingis accomplished by ligation at convenient restriction sites oralternatively via a PCR/recombination method familiar to those skilledin the art (Gateway® Technology; Invitrogen, Carlsbad Calif.). If suchsites do not exist, the synthetic oligonucleotide adapters or linkersare used in accordance with conventional practice.

Promoters are untranslated sequences located upstream (5′) to the startcodon of a structural gene (generally within about 100 to 1000 bp) thatcontrol the transcription and translation of particular nucleic acidsequences to which they are operably linked. Such promoters fall intoseveral classes: inducible, constitutive, and repressible promoters(that increase levels of transcription in response to absence of arepressor). Inducible promoters may initiate increased levels oftranscription from DNA under their control in response to some change inculture conditions, e.g., the presence or absence of a nutrient or achange in temperature.

The yeast promoter fragment may also serve as the site for homologousrecombination and integration of the expression vector into the samesite in the yeast genome; alternatively a selectable marker is used asthe site for homologous recombination. Pichia transformation isdescribed in Cregg et al. (1985) Mol. Cell. Biol. 5:3376-3385.

Examples of suitable promoters from Pichia include the AOX1 and promoter(Cregg et al. (1989) Mol. Cell. Biol. 9:1316-1323); ICL1 promoter(Menendez et al. (2003) Yeast 20(13):1097-108);glyceraldehyde-3-phosphate dehydrogenase promoter (GAP) (Waterham et al.(1997) Gene 186(1):37-44); and FLD1 promoter (Shen et al. (1998) Gene216(1):93-102). The GAP promoter is a strong constitutive promoter andthe AOX and FLD1 promoters are inducible.

Other yeast promoters include ADH1, alcohol dehydrogenase II, GAL4,PHO3, PHO5, Pyk, and chimeric promoters derived therefrom. Additionally,non-yeast promoters may be used in the invention such as mammalian,insect, plant, reptile, amphibian, viral, and avian promoters. Mosttypically the promoter will comprise a mammalian promoter (potentiallyendogenous to the expressed genes) or will comprise a yeast or viralpromoter that provides for efficient transcription in yeast systems.

The polypeptides of interest may be produced recombinantly not onlydirectly, but also as a fusion polypeptide with a heterologouspolypeptide, e.g. a signal sequence or other polypeptide having aspecific cleavage site at the N-terminus of the mature protein orpolypeptide. In general, the signal sequence may be a component of thevector, or it may be a part of the polypeptide coding sequence that isinserted into the vector. The heterologous signal sequence selectedpreferably is one that is recognized and processed through one of thestandard pathways available within the host cell. The S. cerevisiaealpha factor pre-pro signal has proven effective in the secretion of avariety of recombinant proteins from P. pastoris. Other yeast signalsequences include the alpha mating factor signal sequence, the invertasesignal sequence, and signal sequences derived from other secreted yeastpolypeptides. Additionally, these signal peptide sequences may beengineered to provide for enhanced secretion in diploid yeast expressionsystems. Other secretion signals of interest also include mammaliansignal sequences, which may be heterologous to the protein beingsecreted, or may be a native sequence for the protein being secreted.Signal sequences include pre-peptide sequences, and in some instancesmay include propeptide sequences. Many such signal sequences are knownin the art, including the signal sequences found on immunoglobulinchains, e.g., K28 preprotoxin sequence, PHA-E, FACE, human MCP-1, humanserum albumin signal sequences, human Ig heavy chain, human Ig lightchain, and the like. For example, see Hashimoto et. al. Protein Eng11(2) 75 (1998); and Kobayashi et. al. Therapeutic Apheresis 2(4) 257(1998).

Transcription may be increased by inserting a transcriptional activatorsequence into the vector. These activators are cis-acting elements ofDNA, usually about from 10 to 300 bp, which act on a promoter toincrease its transcription. Transcriptional enhancers are relativelyorientation and position independent, having been found 5′ and 3′ to thetranscription unit, within an intron, as well as within the codingsequence itself. The enhancer may be spliced into the expression vectorat a position 5′ or 3′ to the coding sequence, but is preferably locatedat a site 5′ from the promoter.

Expression vectors used in eukaryotic host cells may also containsequences necessary for the termination of transcription and forstabilizing the mRNA. Such sequences are commonly available from 3′ tothe translation termination codon, in untranslated regions of eukaryoticor viral DNAs or cDNAs. These regions contain nucleotide segmentstranscribed as polyadenylated fragments in the untranslated portion ofthe mRNA.

Construction of suitable vectors containing one or more of theabove-listed components employs standard ligation techniques orPCR/recombination methods. Isolated plasmids or DNA fragments arecleaved, tailored, and re-ligated in the form desired to generate theplasmids required or via recombination methods. For analysis to confirmcorrect sequences in plasmids constructed, the ligation mixtures areused to transform host cells, and successful transformants selected byantibiotic resistance (e.g. ampicillin or Zeocin) where appropriate.Plasmids from the transformants are prepared, analyzed by restrictionendonuclease digestion and/or sequenced.

As an alternative to restriction and ligation of fragments,recombination methods based on att sites and recombination enzymes maybe used to insert DNA sequences into a vector. Such methods aredescribed, for example, by Landy (1989) Ann. Rev. Biochem. 58:913-949;and are known to those of skill in the art. Such methods utilizeintermolecular DNA recombination that is mediated by a mixture of lambdaand E. coli-encoded recombination proteins. Recombination occurs betweenspecific attachment (att) sites on the interacting DNA molecules. For adescription of att sites see Weisberg and Landy (1983) Site-SpecificRecombination in Phage Lambda, in Lambda II, Weisberg, ed. (Cold SpringHarbor, N.Y.: Cold Spring Harbor Press), pp. 211-250. The DNA segmentsflanking the recombination sites are switched, such that afterrecombination, the att sites are hybrid sequences comprised of sequencesdonated by each parental vector. The recombination can occur betweenDNAs of any topology.

Att sites may be introduced into a sequence of interest by ligating thesequence of interest into an appropriate vector; generating a PCRproduct containing att B sites through the use of specific primers;generating a cDNA library cloned into an appropriate vector containingatt sites; and the like.

Folding, as used herein, refers to the three-dimensional structure ofpolypeptides and proteins, where interactions between amino acidresidues act to stabilize the structure. While non-covalent interactionsare important in determining structure, usually the proteins of interestwill have intra- and/or intermolecular covalent disulfide bonds formedby two cysteine residues. For naturally occurring proteins andpolypeptides or derivatives and variants thereof, the proper folding istypically the arrangement that results in optimal biological activity,and can conveniently be monitored by assays for activity, e.g. ligandbinding, enzymatic activity, etc.

In some instances, for example where the desired product is of syntheticorigin, assays based on biological activity will be less meaningful. Theproper folding of such molecules may be determined on the basis ofphysical properties, energetic considerations, modeling studies, and thelike.

The expression host may be further modified by the introduction ofsequences encoding one or more enzymes that enhance folding anddisulfide bond formation, i.e. foldases, chaperonins, etc. Suchsequences may be constitutively or inducibly expressed in the yeast hostcell, using vectors, markers, etc. as known in the art. Preferably thesequences, including transcriptional regulatory elements sufficient forthe desired pattern of expression, are stably integrated in the yeastgenome through a targeted methodology.

For example, the eukaryotic PDI is not only an efficient catalyst ofprotein cysteine oxidation and disulfide bond isomerization, but alsoexhibits chaperone activity. Co-expression of PDI can facilitate theproduction of active proteins having multiple disulfide bonds. Also ofinterest is the expression of BIP (immunoglobulin heavy chain bindingprotein); cyclophilin; and the like. In one embodiment of the invention,each of the haploid parental strains expresses a distinct foldingenzyme, e.g. one strain may express BIP, and the other strain mayexpress PDI or combinations thereof.

The terms “desired protein” or “target protein” are used interchangeablyand refer generally to a humanized antibody or a binding portion thereofdescribed herein. The term “antibody” is intended to include anypolypeptide chain-containing molecular structure with a specific shapethat fits to and recognizes an epitope, where one or more non-covalentbinding interactions stabilize the complex between the molecularstructure and the epitope. The archetypal antibody molecule is theimmunoglobulin, and all types of immunoglobulins, IgG, IgM, IgA, IgE,IgD, etc., from all sources, e.g. human, rodent, rabbit, cow, sheep,pig, dog, other mammals, chicken, other avians, etc., are considered tobe “antibodies.” A preferred source for producing antibodies useful asstarting material according to the invention is rabbits. Numerousantibody coding sequences have been described; and others may be raisedby methods well-known in the art. Examples thereof include chimericantibodies, human antibodies and other non-human mammalian antibodies,humanized antibodies, single chain antibodies such as scFvs,camelbodies, nanobodies, IgNAR (single-chain antibodies derived fromsharks), small-modular immunopharmaceuticals (SMIPs), and antibodyfragments such as Fabs, Fab′, F(ab′)₂ and the like. See Streltsov V A,et al., Structure of a shark IgNAR antibody variable domain and modelingof an early-developmental isotype, Protein Sci. 2005 November;14(11):2901-9. Epub 2005 Sep. 30; Greenberg A S, et al., A new antigenreceptor gene family that undergoes rearrangement and extensive somaticdiversification in sharks, Nature. 1995 Mar. 9; 374(6518):168-73;Nuttall S D, et al., Isolation of the new antigen receptor fromwobbegong sharks, and use as a scaffold for the display of protein looplibraries, Mol Immunol. 2001 August; 38(4):313-26; Hamers-Casterman C,et al., Naturally occurring antibodies devoid of light chains, Nature.1993 Jun. 3; 363(6428):446-8; Gill D S, et al., Biopharmaceutical drugdiscovery using novel protein scaffolds, Curr Opin Biotechnol. 2006December; 17(6):653-8. Epub 2006 Oct. 19.

For example, antibodies or antigen binding fragments may be produced bygenetic engineering. In this technique, as with other methods,antibody-producing cells are sensitized to the desired antigen orimmunogen. The messenger RNA isolated from antibody producing cells isused as a template to make cDNA using PCR amplification. A library ofvectors, each containing one heavy chain gene and one light chain generetaining the initial antigen specificity, is produced by insertion ofappropriate sections of the amplified immunoglobulin cDNA into theexpression vectors. A combinatorial library is constructed by combiningthe heavy chain gene library with the light chain gene library. Thisresults in a library of clones which co-express a heavy and light chain(resembling the Fab fragment or antigen binding fragment of an antibodymolecule). The vectors that carry these genes are co-transfected into ahost cell. When antibody gene synthesis is induced in the transfectedhost, the heavy and light chain proteins self-assemble to produce activeantibodies that can be detected by screening with the antigen orimmunogen.

Antibody coding sequences of interest include those encoded by nativesequences, as well as nucleic acids that, by virtue of the degeneracy ofthe genetic code, are not identical in sequence to the disclosed nucleicacids, and variants thereof. Variant polypeptides can include amino acid(aa) substitutions, additions or deletions. The amino acid substitutionscan be conservative amino acid substitutions or substitutions toeliminate non-essential amino acids, such as to alter a glycosylationsite, or to minimize misfolding by substitution or deletion of one ormore cysteine residues that are not necessary for function. Variants canbe designed so as to retain or have enhanced biological activity of aparticular region of the protein (e.g., a functional domain, catalyticamino acid residues, etc). Variants also include fragments of thepolypeptides disclosed herein, particularly biologically activefragments and/or fragments corresponding to functional domains.Techniques for in vitro mutagenesis of cloned genes are known. Alsoincluded in the subject invention are polypeptides that have beenmodified using ordinary molecular biological techniques so as to improvetheir resistance to proteolytic degradation or to optimize solubilityproperties or to render them more suitable as a therapeutic agent.

Chimeric antibodies may be made by recombinant means by combining thevariable light and heavy chain regions (V_(L) and V_(H)), obtained fromantibody producing cells of one species with the constant light andheavy chain regions from another. Typically chimeric antibodies utilizerodent or rabbit variable regions and human constant regions, in orderto produce an antibody with predominantly human domains. The productionof such chimeric antibodies is well known in the art, and may beachieved by standard means (as described, e.g., in U.S. Pat. No.5,624,659, incorporated herein by reference in its entirety). It isfurther contemplated that the human constant regions of chimericantibodies of the invention may be selected from IgG1, IgG2, IgG3, IgG4,IgG5, IgG6, IgG7, IgG8, IgG9, IgG10, IgG11, IgG12, IgG13, IgG14, IgG15,IgG16, IgG17, IgG18 or IgG19 constant regions.

Humanized antibodies are engineered to contain even more human-likeimmunoglobulin domains, and incorporate only thecomplementarity-determining regions of the animal-derived antibody. Thisis accomplished by carefully examining the sequence of thehyper-variable loops of the variable regions of the monoclonal antibody,and fitting them to the structure of the human antibody chains. Althoughfacially complex, the process is straightforward in practice. See, e.g.,U.S. Pat. No. 6,187,287, incorporated fully herein by reference.

In addition to entire immunoglobulins (or their recombinantcounterparts), immunoglobulin fragments comprising the epitope bindingsite (e.g., Fab′, F(ab′)₂, or other fragments) may be synthesized.“Fragment,” or minimal immunoglobulins may be designed utilizingrecombinant immunoglobulin techniques. For instance “Fv” immunoglobulinsfor use in the present invention may be produced by synthesizing a fusedvariable light chain region and a variable heavy chain region.Combinations of antibodies are also of interest, e.g. diabodies, whichcomprise two distinct Fv specificities. In another embodiment of theinvention, SMIPs (small molecule immunopharmaceuticals), camelbodies,nanobodies, and IgNAR are encompassed by immunoglobulin fragments.

Immunoglobulins and fragments thereof may be modifiedpost-translationally, e.g. to add effector moieties such as chemicallinkers, detectable moieties, such as fluorescent dyes, enzymes, toxins,substrates, bioluminescent materials, radioactive materials,chemiluminescent moieties and the like, or specific binding moieties,such as streptavidin, avidin, or biotin, and the like may be utilized inthe methods and compositions of the present invention. Examples ofadditional effector molecules are provided infra.

The term “polyploid yeast that stably expresses or expresses a desiredsecreted heterologous polypeptide for prolonged time” refers to a yeastculture that secretes said polypeptide for at least several days to aweek, more preferably at least a month, still more preferably at least1-6 months, and even more preferably for more than a year at thresholdexpression levels, typically at least 10-25 mg/liter and preferablysubstantially greater.

The term “polyploidal yeast culture that secretes desired amounts ofrecombinant polypeptide” refers to cultures that stably or for prolongedperiods secrete at least 10-25 mg/liter of heterologous polypeptide,more preferably at least 50-500 mg/liter, and most preferably 500-1000mg/liter or more.

A polynucleotide sequence “corresponds” to a polypeptide sequence iftranslation of the polynucleotide sequence in accordance with thegenetic code yields the polypeptide sequence (i.e., the polynucleotidesequence “encodes” the polypeptide sequence), one polynucleotidesequence “corresponds” to another polynucleotide sequence if the twosequences encode the same polypeptide sequence.

A “heterologous” region or domain of a DNA construct is an identifiablesegment of DNA within a larger DNA molecule that is not found inassociation with the larger molecule in nature. Thus, when theheterologous region encodes a mammalian gene, the gene will usually beflanked by DNA that does not flank the mammalian genomic DNA in thegenome of the source organism. Another example of a heterologous regionis a construct where the coding sequence itself is not found in nature(e.g., a cDNA where the genomic coding sequence contains introns, orsynthetic sequences having codons different than the native gene).Allelic variations or naturally-occurring mutational events do not giverise to a heterologous region of DNA as defined herein.

A “coding sequence” is an in-frame sequence of codons that (in view ofthe genetic code) correspond to or encode a protein or peptide sequence.Two coding sequences correspond to each other if the sequences or theircomplementary sequences encode the same amino acid sequences. A codingsequence in association with appropriate regulatory sequences may betranscribed and translated into a polypeptide. A polyadenylation signaland transcription termination sequence will usually be located 3′ to thecoding sequence. A “promoter sequence” is a DNA regulatory regioncapable of binding RNA polymerase in a cell and initiating transcriptionof a downstream (3′ direction) coding sequence. Promoter sequencestypically contain additional sites for binding of regulatory molecules(e.g., transcription factors) which affect the transcription of thecoding sequence. A coding sequence is “under the control” of thepromoter sequence or “operatively linked” to the promoter when RNApolymerase binds the promoter sequence in a cell and transcribes thecoding sequence into mRNA, which is then in turn translated into theprotein encoded by the coding sequence.

Vectors are used to introduce a foreign substance, such as DNA, RNA orprotein, into an organism or host cell. Typical vectors includerecombinant viruses (for polynucleotides) and liposomes (forpolypeptides). A “DNA vector” is a replicon, such as plasmid, phage orcosmid, to which another polynucleotide segment may be attached so as tobring about the replication of the attached segment. An “expressionvector” is a DNA vector which contains regulatory sequences which willdirect polypeptide synthesis by an appropriate host cell. This usuallymeans a promoter to bind RNA polymerase and initiate transcription ofmRNA, as well as ribosome binding sites and initiation signals to directtranslation of the mRNA into a polypeptide(s). Incorporation of apolynucleotide sequence into an expression vector at the proper site andin correct reading frame, followed by transformation of an appropriatehost cell by the vector, enables the production of a polypeptide encodedby said polynucleotide sequence.

“Amplification” of polynucleotide sequences is the in vitro productionof multiple copies of a particular nucleic acid sequence. The amplifiedsequence is usually in the form of DNA. A variety of techniques forcarrying out such amplification are described in a review article by VanBrunt (1990, Bio/Technol., 8(4):291-294). Polymerase chain reaction orPCR is a prototype of nucleic acid amplification, and use of PCR hereinshould be considered exemplary of other suitable amplificationtechniques.

The general structure of antibodies in vertebrates now is wellunderstood (Edelman, G. M., Ann. N.Y. Acad. Sci., 190: 5 (1971)).Antibodies consist of two identical light polypeptide chains ofmolecular weight approximately 23,000 daltons (the “light chain”), andtwo identical heavy chains of molecular weight 53,000-70,000 (the “heavychain”). The four chains are joined by disulfide bonds in a “Y”configuration wherein the light chains bracket the heavy chains startingat the mouth of the “Y” configuration. The “branch” portion of the “Y”configuration is designated the F_(ab) region; the stem portion of the“Y” configuration is designated the F_(c) region. The amino acidsequence orientation runs from the N-terminal end at the top of the “Y”configuration to the C-terminal end at the bottom of each chain. TheN-terminal end possesses the variable region having specificity for theantigen that elicited it, and is approximately 100 amino acids inlength, there being slight variations between light and heavy chain andfrom antibody to antibody.

The variable region is linked in each chain to a constant region thatextends the remaining length of the chain and that within a particularclass of antibody does not vary with the specificity of the antibody(i.e., the antigen eliciting it). There are five known major classes ofconstant regions that determine the class of the immunoglobulin molecule(IgG, IgM, IgA, IgD, and IgE corresponding to γ, μ, α, δ, and ε (gamma,mu, alpha, delta, or epsilon) heavy chain constant regions). Theconstant region or class determines subsequent effector function of theantibody, including activation of complement (Kabat, E. A., StructuralConcepts in Immunology and Immunochemistry, 2nd Ed., p. 413-436, Holt,Rinehart, Winston (1976)), and other cellular responses (Andrews, D. W.,et al., Clinical Immunobiology, pp 1-18, W. B. Sanders (1980); Kohl, S.,et al., Immunology, 48: 187 (1983)); while the variable regiondetermines the antigen with which it will react. Light chains areclassified as either κ (kappa) or λ (lambda). Each heavy chain class canbe paired with either kappa or lambda light chain. The light and heavychains are covalently bonded to each other, and the “tail” portions ofthe two heavy chains are bonded to each other by covalent disulfidelinkages when the immunoglobulins are generated either by hybridomas orby B cells.

The expression “variable region” or “VR” refers to the domains withineach pair of light and heavy chains in an antibody that are involveddirectly in binding the antibody to the antigen. Each heavy chain has atone end a variable domain (V_(H)) followed by a number of constantdomains. Each light chain has a variable domain (V_(L)) at one end and aconstant domain at its other end; the constant domain of the light chainis aligned with the first constant domain of the heavy chain, and thelight chain variable domain is aligned with the variable domain of theheavy chain.

The expressions “complementarity determining region,” “hypervariableregion,” or “CDR” refer to one or more of the hyper-variable orcomplementarity determining regions (CDRs) found in the variable regionsof light or heavy chains of an antibody (See Kabat, E. A. et al.,Sequences of Proteins of Immunological Interest, National Institutes ofHealth, Bethesda, Md., (1987)). These expressions include thehypervariable regions as defined by Kabat et al. (“Sequences of Proteinsof Immunological Interest,” Kabat E., et al., US Dept. of Health andHuman Services, 1983) or the hypervariable loops in 3-dimensionalstructures of antibodies (Chothia and Lesk, J Mol. Biol. 196 901-917(1987)). The CDRs in each chain are held in close proximity by frameworkregions and, with the CDRs from the other chain, contribute to theformation of the antigen binding site. Within the CDRs there are selectamino acids that have been described as the selectivity determiningregions (SDRs) which represent the critical contact residues used by theCDR in the anibody-antigen interaction (Kashmiri, S., Methods, 36:25-34(2005)).

The expressions “framework region” or “FR” refer to one or more of theframework regions within the variable regions of the light and heavychains of an antibody (See Kabat, E. A. et al., Sequences of Proteins ofImmunological Interest, National Institutes of Health, Bethesda, Md.,(1987)). These expressions include those amino acid sequence regionsinterposed between the CDRs within the variable regions of the light andheavy chains of an antibody.

Anti-IL-6 Antibodies and Binding Fragments Thereof

The invention includes antibodies having binding specificity to IL-6 andpossessing a variable light chain sequence comprising the sequence setforth below:

(SEQ ID NO: 2) MDTRAPTQLLGLLLLWLPGARCAYDMTQTPASVSAAVGGTVTIKCQASQSINNELSWYQQKPGQRPKLLIYRASTLASGVSSRFKGSGSGTEFTLTISDLECADAATYYCQQGYSLRNIDNAFGGGTEVVVKRTVAAPSVFIFPPSDEQL KSGTASVVCLLNNand humanized versions thereof including those depicted in FIG. 15. Theinvention also includes antibodies having binding specificity to IL-6and possessing a variable heavy chain sequence comprising the sequenceset forth below:

(SEQ ID NO: 3) METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTASGFSLSNYYVTWVRQAPGKGLEWIGIIYGSDETAYATWAIGRFTISKTSTTVDLKMTSLTAADTATYFCARDDSSDWDAKFNLWGQGTLVTVSSASTKGPSVFPLAPS SKSTSGGTAALGCLVKand humanized versions thereof including those depicted in FIG. 15.

The invention further includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence which is a modifiedversion of SEQ ID NO:3 wherein the tryptophan residue in CDR2 is changedto a serine as set forth below:

(SEQ ID NO: 658) METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTASGFSLSNYYVTWVRQAPGKGLEWIG IIYGSDETAYATSAIG RFTISKTSTTVDLKMTSLTAADTATYFCARDDSSDWDAKFNLWGQGTLVTVSSASTKGPSVFPLAPS SKSTSGGTAALGCLVKand humanized versions thereof including those depicted in FIG. 15.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:4; SEQ ID NO:5; and SEQ ID NO:6which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:2, 20, 647, 648, 649, 650, 651, 660, 666, 699, 702, 706, or 709,and/or one or more of the polypeptide sequences of SEQ ID NO:7; SEQ IDNO:8 or SEQ ID NO:659; and SEQ ID NO:9 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:3, 18, 19, 652, 653, 654,655, 656, 657, 661, 664, 665, 657, 658, 704, or 708, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric or humanized antibodies, comprising one or moreof the polypeptide sequences of SEQ ID NO:4; SEQ ID NO:5; and SEQ IDNO:6 which correspond to the complementarity-determining regions (CDRs,or hypervariable regions) of the variable light chain sequence of SEQ IDNO:2, and/or one or more of the polypeptide sequences of SEQ ID NO:7(CDR1); SEQ ID NO:8 (CDR2); SEQ ID NO:120 (CDR2); SEQ ID NO:659 (CDR2),and SEQ ID NO:9 (CDR3) which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:3 or SEQ ID NO:19, orcombinations of these polypeptide sequences. In another embodiment ofthe invention, the antibodies of the invention include combinations ofthe CDRs and the variable heavy and light chain sequences set forthabove and especially those set forth in FIG. 15.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:2, 20, 647, 648, 649, 650, 651, 660,666, 699, 702, 706, or 709 or humanized versions including those setforth in FIG. 15. In another embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:3, 18, 19, 652, 653, 654, 655, 656,657, 661, 664, 665, 657, 658, 704, or 708 or humanized versionsincluding those set forth in FIG. 15.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:4; SEQ IDNO:5; and SEQ ID NO:6 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:2 or SEQ ID NO:660 or SEQID NO:651 or SEQ ID NO:709 or humanized versions including thosedepicted in FIG. 15.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:7; SEQ ID NO:8or SEQ ID NO:659 or SEQ ID NO:120 and SEQ ID NO:9 which correspond tothe complementarity-determining regions (CDRs, or hypervariable regions)of the variable heavy chain sequence of SEQ ID NO:3 or SEQ ID NO:19.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:2, 20, 647, 648, 649, 650, 651, 660, 666, 699,702, 706, or 709; the variable heavy chain region of SEQ ID NO:3, 18,19, 652, 653, 654, 655, 656, 657, 661, 664, 665, 657, 658, 704, or 708;the complementarity-determining regions (including SEQ ID NO:4; SEQ IDNO:5; and SEQ ID NO:6) of the variable light chain region of SEQ IDNO:2, 20, 647, 648, 649, 650, 651, 660, 666, 699, 702, 706, or 709; andthe complementarity-determining regions (including SEQ ID NO:7; SEQ IDNO:8 or SEQ ID NO:120 or SEQ ID NO:659; and SEQ ID NO:9) of the variableheavy chain region of SEQ ID NO:3, 18, 19, 652, 653, 654, 655, 656, 657,661, 664, 665, 657, 658, 704, or 708.

The invention also contemplates variants wherein either of the heavychain polypeptide sequences of SEQ ID NO:18, 19, 652, 653, 654, 655,656, 657, 661, 664, 665, 657, 658, 704, or 708 is substituted for theheavy chain polypeptide sequence of SEQ ID NO:3; the light chainpolypeptide sequence of SEQ ID NO:20, 647, 648, 649, 650, 651, 660, 666,699, 702, 706, or 709 is substituted for the light chain polypeptidesequence of SEQ ID NO:2; and the heavy chain CDR sequence of SEQ IDNO:120 is substituted for the heavy chain CDR sequence of SEQ ID NO:8 orSEQ ID NO:659.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb1, comprising SEQ ID NO:2, 20, 647, 648, 649, 650, 651, 660, 666, 699,702, 706, or 709 and SEQ ID NO:3, 18, 19, 652, 653, 654, 655, 656, 657,661, 664, 665, 657, 658, 704, or 708 or an antibody comprising anycombination of the variable heavy and light chain region sequencesdepicted in FIG. 15 or FIG. 16 especially one comprising the variablelight region in SEQ ID NO:651 or SEQ ID NO:709 and the heavy region inor SEQ ID NO:656 or SEQ ID NO:657 or SEQ ID NO:658 or the alternativeSEQ ID NOs set forth above, and having at least one of the biologicalactivities set forth herein.

In another embodiment the anti-IL-6 antibody of the invention is onecomprising at least one of the following: a CDR1 light chain encoded bythe sequence in SEQ ID NO:12 or SEQ ID NO:694; a light chain CDR2encoded by the sequence in SEQ ID NO:13; a light chain CDR3 encoded bythe sequence in SEQ ID NO:14 or SEQ ID NO:695; a heavy chain CDR1encoded by the sequence in SEQ ID NO:15, a heavy chain CDR2 encoded bySEQ ID NO:16 or SEQ ID NO:696 and a heavy chain CDR3 encoded by SEQ IDNO:17 or SEQ ID NO:697. In addition the invention embraces such nucleicacid sequences and variants thereof.

In another embodiment the invention is directed to amino acid sequencescorresponding to the CDRs of said anti-IL-6 antibody which are selectedfrom SEQ ID NO:4 (CDR1), SEQ ID NO:5 (CDR2), SEQ ID NO:6 (CDR3), SEQ IDNO:7, SEQ ID NO:120 and SEQ ID NO:9.

In another embodiment the anti-IL-6 antibody of the invention comprisesa light chain encoded by the nucleic acid sequence in SEQ ID NO:10 orSEQ ID NO:698 or SEQ ID NO:701 or SEQ ID NO:705 and/or a heavy chainencoded by a nucleic acid sequence in SEQ ID NO:11 or SEQ ID NO:700 orSEQ ID NO:703 or SEQ ID NO:707. In addition the invention is directed tothe corresponding polypeptides encoded by any of the foregoing nucleicacid sequences and combinations thereof.

In a specific embodiment of the invention the anti-IL-6 antibodies or aportion thereof will be encoded by a nucleic acid sequence selected fromthose comprised in SEQ ID NO:12, 694, 13, 14, 695, 15, 16, 696, 697,698, 10, 11, 700, 10, 701, 11, 703, 705 and 707. For example the CDR1 inthe light chain may be encoded by SEQ ID NO:12 or 694, the CDR2 in thelight chain may be encoded by SEQ ID NO:13, the CDR3 in the light chainmay be encoded by SEQ ID NO:14 or 695; the CDR1 in the heavy chain maybe encoded by SEQ ID NO:15, the CDR2 in the heavy chain may be encodedby SEQ ID NO:16 or 696, the CDR3 in the heavy chain may be encoded bySEQ ID NO: 17 or 697. As discussed infra antibodies containing theseCDRs may be constructed using appropriate human frameworks based on thehumanization methods disclosed herein.

In another specific embodiment of the invention the variable light chainwill be encoded by SEQ ID NO:10 or SEQ ID NO:698 or SEQ ID NO:701 or SEQID NO:705 and the variable heavy chain of the anti-IL-6 antibodies willbe encoded by SEQ ID NO:11, SEQ ID NO:700 or SEQ ID NO:703 or SEQ IDNO:707.

In a more specific embodiment variable light and heavy chains of theanti-IL-6 antibody respectively will be encoded by SEQ ID NO:10 and 11,or SEQ ID NO:698 and SEQ ID NO:700, or SEQ ID NO:701 and SEQ ID NO:703or SEQ ID NO:705 and SEQ ID NO:707.

In another specific embodiment the invention covers nucleic acidconstructs containing any of the foregoing nucleic acid sequences andcombinations thereof as well as recombinant cells containing thesenucleic acid sequences and constructs containing wherein these nucleicacid sequences or constructs may be extrachromosomal or integrated intothe host cell genome.

In another specific embodiment the invention covers polypeptidescontaining any of the CDRs or combinations thereof recited in SEQ IDNO:4, SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:120,SEQ ID NO:9 or polypeptides comprising any of the variable lightpolypeptides comprised in SEQ ID NO:2, 20, 647, 648, 649, 650, 651, 660,666, 699, 702, 706, or 709 and/or the variable heavy polypeptidescomprised in SEQ ID NO:3, 18, 19, 652, 653, 654, 655, 656, 657, 661,664, 665, 657, 658, 704, or 708. These polypeptides optionally may beattached directly or indirectly to other immunoglobulin polypeptides oreffector moieties such as therapeutic or detectable entities.

In another embodiment the anti-IL-6 antibody is one comprising at leastone of the following: a variable light chain encoded by the sequence inSEQ ID NO:10 or SEQ ID NO:698 or SEQ ID NO:701 or SEQ ID NO:705 and avariable chain encoded by the sequence in SEQ ID NO:11 or SEQ ID NO:700or SEQ ID NO:703 or SEQ ID NO:707.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below or in SEQ ID NO:667:

(SEQ ID NO: 21) MDTRAPTQLLGLLLLWLPGARCAYDMTQTPASVEVAVGGTVTINCQASETIYSWLSWYQQKPGQPPKLLIYQASDLASGVPSRFSGSGAGTEYTLTISGVQCDDAATYYCQQGYSGSNVDNVFGGGTEVVVKRTVAAPSVFIFPPSDEQL KSGTASVVCLLNNFY

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below or as in SEQ ID NO:668:

(SEQ ID NO: 22) METGLRWLLLVAVLKGVQCQEQLKESGGRLVTPGTPLTLTCTASGFSLNDHAMGWVRQAPGKGLEYIGFINSGGSARYASWAEGRFTISRTSTTVDLKMTSLTTEDTATYFCVRGGAVWSIHSFDPWGPGTLVTVSSASTKGPSVFPL APSSKSTSGGTAALGCLVK.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:23; SEQ ID NO:24; and SEQ IDNO:25 which correspond to the complementarity-determining regions (CDRs,or hypervariable regions) of the variable light chain sequence of SEQ IDNO:21 or SEQ ID NO:667, and/or one or more of the polypeptide sequencesof SEQ ID NO:26; SEQ ID NO:27; and SEQ ID NO:28 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:22, SEQ ID NO:668, orcombinations of these polypeptide sequences. In another embodiment ofthe invention, the antibodies of the invention include combinations ofthe CDRs and the variable heavy and light chain sequences set forthabove.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:23; SEQ ID NO:24; and SEQ ID NO:25which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:21 or SEQ ID NO:667, and/or one or more of the polypeptide sequencesof SEQ ID NO:26; SEQ ID NO:27; and SEQ ID NO:28 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:22 or SEQ ID NO:668, orcombinations of these polypeptide sequences. In another embodiment ofthe invention, the antibodies of the invention include combinations ofthe CDRs and the variable heavy and light chain sequences set forthabove.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:21 or SEQ ID NO:667. In anotherembodiment of the invention, antibody fragments of the inventioncomprise, or alternatively consist of, the polypeptide sequence of SEQID NO:22 or SEQ ID NO:668.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:23; SEQ IDNO:24; and SEQ ID NO:25 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:21 or SEQ ID NO:667.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:26; SEQ IDNO:27; and SEQ ID NO:28 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:22 or SEQ ID NO:668.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:21 or SEQ ID NO:667; the variable heavy chainregion of SEQ ID NO:22 or SEQ ID NO:668; the complementarity-determiningregions (SEQ ID NO:23; SEQ ID NO:24; and SEQ ID NO:25) of the variablelight chain region of SEQ ID NO:21 or SEQ ID NO:667; and thecomplementarity-determining regions (SEQ ID NO:26; SEQ ID NO:27; and SEQID NO:28) of the variable heavy chain region of SEQ ID NO:22 or SEQ IDNO:668.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb2, comprising SEQ ID NO:21 or SEQ ID NO:667 and SEQ ID NO:22 or SEQ IDNO:668, and having at least one of the biological activities set forthherein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below or the sequence of SEQ IDNO:671:

(SEQ ID NO: 37) MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSPVSAAVGGTVSISCQASQSVYDNNYLSWFQQKPGQPPKLLIYGASTLASGVPSRFVGSGSGTQFTLTITDVQCDDAATYYCAGVYDDDSDNAFGGGTEVVVKRTVAAPSVFIFPPSD EQLKSGTASVVCLLNN

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below or the sequence of SEQ ID NO: 672:

(SEQ ID NO: 38) METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTASGFSLSVYYMNWVRQAPGKGLEWIGFITMSDNINYASWAKGRFTISKTSTTVDLKMTSPTTEDTATYFCARSRGWGTMGRLDLWGPGTLVTVSSASTKGPSVFPLA PSSKSTSGGTAALGCLVK.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:39; SEQ ID NO:40; and SEQ IDNO:41 which correspond to the complementarity-determining regions (CDRs,or hypervariable regions) of the variable light chain sequence of SEQ IDNO:37 or SEQ ID NO:671, and/or one or more of the polypeptide sequencesof SEQ ID NO:42; SEQ ID NO:43; and SEQ ID NO:44 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:38 or SEQ ID NO:672, orcombinations of these polypeptide sequences. In another embodiment ofthe invention, the antibodies of the invention include combinations ofthe CDRs and the variable heavy and light chain sequences set forthabove.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:39; SEQ ID NO:40; and SEQ ID NO:41which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:37 or SEQ ID NO:671, and/or one or more of the polypeptide sequencesof SEQ ID NO:42; SEQ ID NO:43; and SEQ ID NO:44 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:38 or SEQ ID NO:672, orcombinations of these polypeptide sequences. In another embodiment ofthe invention, the antibodies of the invention include combinations ofthe CDRs and the variable heavy and light chain sequences set forthabove.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:37 or SEQ ID NO:671. In anotherembodiment of the invention, antibody fragments of the inventioncomprise, or alternatively consist of, the polypeptide sequence of SEQID NO:38 or 672.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:39; SEQ IDNO:40; and SEQ ID NO:41 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:37 or SEQ ID NO:671.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:42; SEQ IDNO:43; and SEQ ID NO:44 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:38 OR 672.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:37 or SEQ ID NO:671; the variable heavy chainregion of SEQ ID NO:38 OR 672; the complementarity-determining regions(SEQ ID NO:39; SEQ ID NO:40; and SEQ ID NO:41) of the variable lightchain region of SEQ ID NO:37 or SEQ ID NO:671; and thecomplementarity-determining regions (SEQ ID NO:42; SEQ ID NO:43; and SEQID NO:44) of the variable heavy chain region of SEQ ID NO:38 OR 672.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb3, comprising SEQ ID NO:37 or SEQ ID NO:671 and SEQ ID NO:38 or SEQ IDNO:672, and having at least one of the biological activities set forthherein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below or the sequence of SEQ IDNO:675:

(SEQ ID NO: 53) MDTRAPTQLLGLLLLWLPGAICDPVLTQTPSPVSAPVGGTVSISCQASQSVYENNYLSWFQQKPGQPPKLLIYGASTLDSGVPSRFKGSGSGTQFTLTITDVQCDDAATYYCAGVYDDDSDDAFGGGTEVVVKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNN

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below or the sequence of SEQ ID NO:676:

(SEQ ID NO: 54) METGLRWLLLVAVLKGVQCQEQLKESGGGLVTPGGTLTLTCTASGFSLNAYYMNWVRQAPGKGLEWIGFITLNNNVAYANWAKGRFTFSKTSTTVDLKMTSPTPEDTATYFCARSRGWGAMGRLDLWGHGTLVTVSSASTKGPSVFPLAP SSKSTSGGTAALGCLVK.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:55; SEQ ID NO:56; and SEQ IDNO:57 which correspond to the complementarity-determining regions (CDRs,or hypervariable regions) of the variable light chain sequence of SEQ IDNO:53 or SEQ ID NO:675, and/or one or more of the polypeptide sequencesof SEQ ID NO:58; SEQ ID NO:59; and SEQ ID NO:60 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:54 or SEQ ID NO:676, orcombinations of these polypeptide sequences. In another embodiment ofthe invention, the antibodies of the invention include combinations ofthe CDRs and the variable heavy and light chain sequences set forthabove.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:55; SEQ ID NO:56; and SEQ ID NO:57which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:53 or SEQ ID NO:675, and/or one or more of the polypeptide sequencesof SEQ ID NO:58; SEQ ID NO:59; and SEQ ID NO:60 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:54 or SEQ ID NO:676, orcombinations of these polypeptide sequences. In another embodiment ofthe invention, the antibodies of the invention include combinations ofthe CDRs and the variable heavy and light chain sequences set forthabove.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:53 or SEQ ID NO:675. In anotherembodiment of the invention, antibody fragments of the inventioncomprise, or alternatively consist of, the polypeptide sequence of SEQID NO:54 or SEQ ID NO:676.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:55; SEQ IDNO:56; and SEQ ID NO:57 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:53 or SEQ ID NO:675.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:58; SEQ IDNO:59; and SEQ ID NO:60 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:54 or SEQ ID NO:676.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:53 or SEQ ID NO:675; the variable heavy chainregion of SEQ ID NO:54 or SEQ ID NO:676; the complementarity-determiningregions (SEQ ID NO:55; SEQ ID NO:56; and SEQ ID NO:57) of the variablelight chain region of SEQ ID NO:53 or SEQ ID NO:675; and thecomplementarity-determining regions (SEQ ID NO:58; SEQ ID NO:59; and SEQID NO:60) of the variable heavy chain region of SEQ ID NO:54 or SEQ IDNO:676.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb4, comprising SEQ ID NO:53 or SEQ ID NO:675 and SEQ ID NO:54 or SEQ IDNO:676, and having at least one of the biological activities set forthherein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below or the polypeptide sequence ofSEQ ID NO:679:

(SEQ ID NO: 69) MDTRAPTQLLGLLLLWLPGATFAQVLTQTPSPVSAAVGGTVTINCQASQSVDDNNWLGWYQQKRGQPPKYLIYSASTLASGVPSRFKGSGSGTQFTLTISDLECDDAATYYCAGGFSGNIFAFGGGTEVVVKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNF

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below or the polypeptide of SEQ ID NO:680:

(SEQ ID NO: 70) METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTVSGFSLSSYAMSWVRQAPGKGLEWIGIIGGFGTTYYATWAKGRFTISKTSTTVDLRITSPTTEDTATYFCARGGPGNGGDIWGQGTLVTVSSASTKGPSVFPLAPSSKS TSGGTAALGCLVKD.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:71; SEQ ID NO:72; and SEQ IDNO:73 which correspond to the complementarity-determining regions (CDRs,or hypervariable regions) of the variable light chain sequence of SEQ IDNO:69 or SEQ ID NO:679, and/or one or more of the polypeptide sequencesof SEQ ID NO:74; SEQ ID NO:75; and SEQ ID NO:76 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:70 or SEQ ID NO:680, orcombinations of these polypeptide sequences. In another embodiment ofthe invention, the antibodies of the invention include combinations ofthe CDRs and the variable heavy and light chain sequences set forthabove.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:71; SEQ ID NO:72; and SEQ ID NO:73which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:69 or SEQ ID NO:679 and/or one or more of the polypeptide sequencesof SEQ ID NO:74; SEQ ID NO:75; and SEQ ID NO:76 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:70 or SEQ ID NO:680, orcombinations of these polypeptide sequences. In another embodiment ofthe invention, the antibodies of the invention include combinations ofthe CDRs and the variable heavy and light chain sequences set forthabove.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:69 OR 679. In another embodiment ofthe invention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:70 OR680.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:71; SEQ IDNO:72; and SEQ ID NO:73 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:69 OR 679.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:74; SEQ IDNO:75; and SEQ ID NO:76 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:70 OR 680.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:69 OR 679; the variable heavy chain region ofSEQ ID NO:70 OR 680; the complementarity-determining regions (SEQ IDNO:71; SEQ ID NO:72; and SEQ ID NO:73) of the variable light chainregion of SEQ ID NO:69 OR 679; and the complementarity-determiningregions (SEQ ID NO:74; SEQ ID NO:75; and SEQ ID NO:76) of the variableheavy chain region of SEQ ID NO:70 OR 680.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb5, comprising SEQ ID NO:69 OR 679 and SEQ ID NO:70 or SEQ ID NO:680,and having at least one of the biological activities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below or the polypeptide of SEQ IDNO:683:

(SEQ ID NO: 85) MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSPVSVPVGGTVTIKCQSSQSVYNNFLSWYQQKPGQPPKLLIYQASKLASGVPDRFSGSGSGTQFTLTISGVQCDDAATYYCLGGYDDDADNAFGGGTEVVVKRTVAAPSVFIFPPSDE QLKSGTASVVCLLNNF

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below or the polypeptide of SEQ ID NO:684:

(SEQ ID NO: 86) METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTVSGIDLSDYAMSWVRQAPGKGLEWIGIIYAGSGSTWYASWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARDGYDDYGDFDRLDLWGPGTLVTVSSASTKGPSVFPL APSSKSTSGGTAALGCLVKD.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:87; SEQ ID NO:88; and SEQ IDNO:89 which correspond to the complementarity-determining regions (CDRs,or hypervariable regions) of the variable light chain sequence of SEQ IDNO:85 or SEQ ID NO:683, and/or one or more of the polypeptide sequencesof SEQ ID NO:90; SEQ ID NO:91; and SEQ ID NO:92 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:86 or SEQ ID NO:684, orcombinations of these polypeptide sequences. In another embodiment ofthe invention, the antibodies of the invention include combinations ofthe CDRs and the variable heavy and light chain sequences set forthabove.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:87; SEQ ID NO:88; and SEQ ID NO:89which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:85 or SEQ ID NO:683, and/or one or more of the polypeptide sequencesof SEQ ID NO:90; SEQ ID NO:91; and SEQ ID NO:92 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:86 or SEQ ID NO:684, orcombinations of these polypeptide sequences. In another embodiment ofthe invention, the antibodies of the invention include combinations ofthe CDRs and the variable heavy and light chain sequences set forthabove.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:85 or SEQ ID NO:683. In anotherembodiment of the invention, antibody fragments of the inventioncomprise, or alternatively consist of, the polypeptide sequence of SEQID NO:86 OR 684.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:87; SEQ IDNO:88; and SEQ ID NO:89 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:85 or SEQ ID NO:683.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:90; SEQ IDNO:91; and SEQ ID NO:92 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:86 OR 684.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:85 or SEQ ID NO:683; the variable heavy chainregion of SEQ ID NO:86 OR 684; the complementarity-determining regions(SEQ ID NO:87; SEQ ID NO:88; and SEQ ID NO:89) of the variable lightchain region of SEQ ID NO:85 or SEQ ID NO:683; and thecomplementarity-determining regions (SEQ ID NO:90; SEQ ID NO:91; and SEQID NO:92) of the variable heavy chain region of SEQ ID NO:86 OR 684.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb6, comprising SEQ ID NO:85 or SEQ ID NO:683 and SEQ ID NO:86 or SEQ IDNO:684, and having at least one of the biological activities set forthherein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below or the polypeptide of SEQ ID NO:119, 687, 693:

(SEQ ID NO: 101) MDTRAPTQLLGLLLLWLPGARCAYDMTQTPASVSAAVGGTVTIKCQASQSINNELSWYQQKSGQRPKLLIYRASTLASGVSSRFKGSGSGTEFTLTISDLECADAATYYCQQGYSLRNIDNAFGGGTEVVVKRTVAAPSVFIFPPSD EQLKSGTASVVCLLNNF

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below or the polypeptide of SEQ ID NO:117, 118, 688,691, or 692:

(SEQ ID NO: 102) METGLRWLLLVAVLSGVQCQSLEESGGRLVTPGTPLTLTCTASGFSLSNYYMTWVRQAPGKGLEWIGMIYGSDETAYANWAIGRFTISKTSTTVDLKMTSLTAADTATYFCARDDSSDWDAKFNLWGQGTLVTVSSASTKGPSVFPLAPS SKSTSGGTAALGCLVK.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:103; SEQ ID NO:104; and SEQ IDNO:105 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:101, 119, 687, or 693; and/or one or more of the polypeptidesequences of SEQ ID NO:106; SEQ ID NO:107; and SEQ ID NO:108 whichcorrespond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable heavy chain sequence of SEQ IDNO:102, 117, 118, 688, 691, or 692, or combinations of these polypeptidesequences. In another embodiment of the invention, the antibodies of theinvention include combinations of the CDRs and the variable heavy andlight chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:103; SEQ ID NO:104; and SEQ ID NO:105which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:101, 119, 687, or 693, and/or one or more of the polypeptidesequences of SEQ ID NO:106; SEQ ID NO:107; and SEQ ID NO:108 whichcorrespond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable heavy chain sequence of SEQ IDNO:102, 117, 118, 688, 691, or 692, or combinations of these polypeptidesequences. In another embodiment of the invention, the antibodies of theinvention include combinations of the CDRs and the variable heavy andlight chain sequences set forth above.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:101, 119, 687, or 693. In anotherembodiment of the invention, antibody fragments of the inventioncomprise, or alternatively consist of, the polypeptide sequence of SEQID NO:102, 117, 118, 688, 691, or 692.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:103; SEQ IDNO:104; and SEQ ID NO:105 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:101, 119, 687, or 693.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:106; SEQ IDNO:107; and SEQ ID NO:108 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:102, 117, 118, 688, 691,or 692.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:101, 119, 687, or 693; the variable heavychain region of SEQ ID NO:102, 117, 118, 688, 691, or 692; thecomplementarity-determining regions (SEQ ID NO:103; SEQ ID NO:104; andSEQ ID NO:105) of the variable light chain region of SEQ ID NO:101, 119,687, or 693; and the complementarity-determining regions (SEQ ID NO:106;SEQ ID NO:107; and SEQ ID NO:108) of the variable heavy chain region ofSEQ ID NO:102, 117, 118, 688, 691, or 692.

The invention also contemplates variants wherein either of the heavychain polypeptide sequences of SEQ ID NO:117 or SEQ ID NO:691 or SEQ IDNO:118 or SEQ ID NO:692 is substituted for the heavy chain polypeptidesequence of SEQ ID NO:102, 117, 118, 688, 691, or 692; the light chainpolypeptide sequence of SEQ ID NO:119 or SEQ ID NO:693 is substitutedfor the light chain polypeptide sequence of SEQ ID NO:101, 119, 687, or693; and the heavy chain CDR sequence of SEQ ID NO:121 is substitutedfor the heavy chain CDR sequence of SEQ ID NO:107.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb7, comprising SEQ ID NO:101, 119, 687, or 693 and SEQ ID NO:102, 117,118, 688, 691, or 692, or the alternative SEQ ID NOs set forth in theprevious paragraph above, and having at least one of the biologicalactivities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 122) MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSPVSAAVGGTVTISCQSSQSVGNNQDLSWFQQRPGQPPKLLIYEISKLESGVPSRFSGSGSGTHFTLTISGVQCDDAATYYCLGGYDDDADNA

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below:

(SEQ ID NO: 123) METGLRWLLLVAVLKGVQCHSVEESGGRLVTPGTPLTLTCTVSGFSLSSRTMSWVRQAPGKGLEWIGYIWSGGSTYYATWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARLGDTGGHAYATRLNL.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:124; SEQ ID NO:125; and SEQ IDNO:126 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:122, and/or one or more of the polypeptide sequences of SEQ IDNO:127; SEQ ID NO:128; and SEQ ID NO:129 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:123, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:124; SEQ ID NO:125; and SEQ ID NO:126which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:122, and/or one or more of the polypeptide sequences of SEQ IDNO:127; SEQ ID NO:128; and SEQ ID NO:129 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:123, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:122. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:123.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:124; SEQ IDNO:125; and SEQ ID NO:126 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:122.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:127; SEQ IDNO:128; and SEQ ID NO:129 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:123.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:122; the variable heavy chain region of SEQ IDNO:123; the complementarity-determining regions (SEQ ID NO:124; SEQ IDNO:125; and SEQ ID NO:126) of the variable light chain region of SEQ IDNO:122; and the complementarity-determining regions (SEQ ID NO:127; SEQID NO:128; and SEQ ID NO:129) of the variable heavy chain region of SEQID NO:123.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb8, comprising SEQ ID NO:122 and SEQ ID NO:123, and having at least oneof the biological activities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 138) MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSSVSAAVGGTVSISCQSSQSVYSNKYLAWYQQKPGQPPKLLIYWTSKLASGAPSRFSGSGSGTQFTLTISGVQCDDAATYYCLGAYDDDADNA

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below:

(SEQ ID NO: 139) METGLRWLLLVAVLKGVQCQSVEESGGRLVKPDETLTLTCTASGFSLEGGYMTWVRQAPGKGLEWIGISYDSGSTYYASWAKGRFTISKTSSTTVDLKMTSLTTEDTATYFCVRSLKYPTVTSDDL.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:140; SEQ ID NO:141; and SEQ IDNO:142 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:138, and/or one or more of the polypeptide sequences of SEQ IDNO:143; SEQ ID NO:144; and SEQ ID NO:145 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:139, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:140; SEQ ID NO:141; and SEQ ID NO:142which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:138, and/or one or more of the polypeptide sequences of SEQ IDNO:143; SEQ ID NO:144; and SEQ ID NO:145 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:139, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:138. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:139.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:140; SEQ IDNO:141; and SEQ ID NO:142 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:138.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:143; SEQ IDNO:144; and SEQ ID NO:145 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:139.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:138; the variable heavy chain region of SEQ IDNO:139; the complementarity-determining regions (SEQ ID NO:140; SEQ IDNO:141; and SEQ ID NO:142) of the variable light chain region of SEQ IDNO:138; and the complementarity-determining regions (SEQ ID NO:143; SEQID NO:144; and SEQ ID NO:145) of the variable heavy chain region of SEQID NO:139.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb9, comprising SEQ ID NO:138 and SEQ ID NO:139, and having at least oneof the biological activities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 154) MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSPVSAAVGGTVTISCQSSQSVYNNNDLAWYQQKPGQPPKLLIYYASTLASGVPSRFKGSGSGTQFTLTISGVQCDDAAAYYCLGGYDDDADNA

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below:

(SEQ ID NO: 155) METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTVSGLSLSSNTINWVRQAPGKGLEWIGYIWSGGSTYYASWVNGRFTISKTSTTVDLKITSPTTEDTATYFCARGGYASGGYPYATRLDL.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:156; SEQ ID NO:157; and SEQ IDNO:158 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:154, and/or one or more of the polypeptide sequences of SEQ IDNO:159; SEQ ID NO:160; and SEQ ID NO:161 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:155, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:156; SEQ ID NO:157; and SEQ ID NO:158which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:154, and/or one or more of the polypeptide sequences of SEQ IDNO:159; SEQ ID NO:160; and SEQ ID NO:161 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:155, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:154. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:155.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:156; SEQ IDNO:157; and SEQ ID NO:158 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:154.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:159; SEQ IDNO:160; and SEQ ID NO:161 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:155.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:154; the variable heavy chain region of SEQ IDNO:155; the complementarity-determining regions (SEQ ID NO:156; SEQ IDNO:157; and SEQ ID NO:158) of the variable light chain region of SEQ IDNO:154; and the complementarity-determining regions (SEQ ID NO:159; SEQID NO:160; and SEQ ID NO:161) of the variable heavy chain region of SEQID NO:155.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb10, comprising SEQ ID NO:154 and SEQ ID NO:155, and having at leastone of the biological activities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 170) MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSSVSAAVGGTVTINCQSSQSVYNNDYLSWYQQRPGQRPKLLIYGASKLASGVPSRFKGSGSGKQFTLTISGVQCDDAATYYCLGDYDDDADNT

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below:

(SEQ ID NO: 171) METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTVSGFTLSTNYYLSWVRQAPGKGLEWIGIIYPSGNTYCAKWAKGRFTISKTSSTTVDLKMTSPTTEDTATYFCARNYGGDESL.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:172; SEQ ID NO:173; and SEQ IDNO:174 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:170, and/or one or more of the polypeptide sequences of SEQ IDNO:175; SEQ ID NO:176; and SEQ ID NO:177 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:171, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:172; SEQ ID NO:173; and SEQ ID NO:174which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:170, and/or one or more of the polypeptide sequences of SEQ IDNO:175; SEQ ID NO:176; and SEQ ID NO:177 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:171, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:170. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:171.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:172; SEQ IDNO:173; and SEQ ID NO:174 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:170.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:175; SEQ IDNO:176; and SEQ ID NO:177 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:171.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:170; the variable heavy chain region of SEQ IDNO:171; the complementarity-determining regions (SEQ ID NO:172; SEQ IDNO:173; and SEQ ID NO:174) of the variable light chain region of SEQ IDNO:170; and the complementarity-determining regions (SEQ ID NO:175; SEQID NO:176; and SEQ ID NO:177) of the variable heavy chain region of SEQID NO:171.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb11, comprising SEQ ID NO:170 and SEQ ID NO:171, and having at leastone of the biological activities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 186) MDTRAPTQLLGLLLLWLPGARCDVVMTQTPASVEAAVGGTVTIKCQASETIGNALAWYQQKSGQPPKLLIYKASKLASGVPSRFKGSGSGTEYTLTISDLECADAATYYCQWCYFGDSV

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below:

(SEQ ID NO: 187) METGLRWLLLVTVLKGVQCQEQLVESGGGLVQPEGSLTLTCTASGFDFSSGYYMCWVRQAPGKGLEWIACIFTITTNTYYASWAKGRFTISKTSSTTVTLQMTSLTAADTATYLCARGIYSDNNYYAL.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:188; SEQ ID NO:189; and SEQ IDNO:190 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:186, and/or one or more of the polypeptide sequences of SEQ IDNO:191; SEQ ID NO:192; and SEQ ID NO:193 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:187, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:188; SEQ ID NO:189; and SEQ ID NO:190which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:186, and/or one or more of the polypeptide sequences of SEQ IDNO:191; SEQ ID NO:192; and SEQ ID NO:193 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:187, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:186. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:187.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:188; SEQ IDNO:189; and SEQ ID NO:190 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:186.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:191; SEQ IDNO:192; and SEQ ID NO:193 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:187.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:186; the variable heavy chain region of SEQ IDNO:187; the complementarity-determining regions (SEQ ID NO:188; SEQ IDNO:189; and SEQ ID NO:190) of the variable light chain region of SEQ IDNO:186; and the complementarity-determining regions (SEQ ID NO:191; SEQID NO:192; and SEQ ID NO:193) of the variable heavy chain region of SEQID NO:187.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb12, comprising SEQ ID NO:186 and SEQ ID NO:187, and having at leastone of the biological activities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 202) MDTRAPTQLLGLLLLWLPGARCDVVMTQTPASVEAAVGGTVTIKCQASESIGNALAWYQQKPGQPPKLLIYKASTLASGVPSRFSGSGSGTEFTLTISGVQCADAAAYYCQWCYFGDSV

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below:

(SEQ ID NO: 203) METGLRWLLLVAVLKGVQCQQQLVESGGGLVKPGASLTLTCKASGFSFSSGYYMCWVRQAPGKGLESIACIFTITDNTYYANWAKGRFTISKPSSPTVTLQMTSLTAADTATYFCARGIYSTDNYYAL.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:204; SEQ ID NO:205; and SEQ IDNO:206 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:202, and/or one or more of the polypeptide sequences of SEQ IDNO:207; SEQ ID NO:208; and SEQ ID NO:209 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:203, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:204; SEQ ID NO:205; and SEQ ID NO:206which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:202, and/or one or more of the polypeptide sequences of SEQ IDNO:207; SEQ ID NO:208; and SEQ ID NO:209 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:203, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:202. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:203.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:204; SEQ IDNO:205; and SEQ ID NO:206 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:202.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:207; SEQ IDNO:208; and SEQ ID NO:209 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:203.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:202; the variable heavy chain region of SEQ IDNO:203; the complementarity-determining regions (SEQ ID NO:204; SEQ IDNO:205; and SEQ ID NO:206) of the variable light chain region of SEQ IDNO:202; and the complementarity-determining regions (SEQ ID NO:207; SEQID NO:208; and SEQ ID NO:209) of the variable heavy chain region of SEQID NO:203.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb13, comprising SEQ ID NO:202 and SEQ ID NO:203, and having at leastone of the biological activities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 218) MDTRAPTQLLGLLLLWLPGARCDVVMTQTPASVEAAVGGTVTIKCQASQSVSSYLNWYQQKPGQPPKLLIYRASTLESGVPSRFKGSGSGTEFTLTISDLECADAATYYCQCTYGTSSSYGAA

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below:

(SEQ ID NO: 219) METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTVSGISLSSNAISWVRQAPGKGLEWIGIISYSGTTYYASWAKGRFTISKTSSTTVDLKITSPTTEDTATYFCARDDPTTVMVMLIPFGAGMDL.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:220; SEQ ID NO:221; and SEQ IDNO:222 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:218, and/or one or more of the polypeptide sequences of SEQ IDNO:223; SEQ ID NO:224; and SEQ ID NO:225 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:219, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:220; SEQ ID NO:221; and SEQ ID NO:222which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:218, and/or one or more of the polypeptide sequences of SEQ IDNO:223; SEQ ID NO:224; and SEQ ID NO:225 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:219, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:218. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:219.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:220; SEQ IDNO:221; and SEQ ID NO:222 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:218.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:223; SEQ IDNO:224; and SEQ ID NO:225 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:219.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:218; the variable heavy chain region of SEQ IDNO:219; the complementarity-determining regions (SEQ ID NO:220; SEQ IDNO:221; and SEQ ID NO:222) of the variable light chain region of SEQ IDNO:218; and the complementarity-determining regions (SEQ ID NO:223; SEQID NO:224; and SEQ ID NO:225) of the variable heavy chain region of SEQID NO:219.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb14, comprising SEQ ID NO:218 and SEQ ID NO:219, and having at leastone of the biological activities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 234) MDTRAPTQLLGLLLLWLPGATFAQVLTQTASPVSAAVGGTVTINCQASQSVYKNNYLSWYQQKPGQPPKGLIYSASTLDSGVPLRFSGSGSGTQFTLTISDVQCDDAATYYCLGSYDCSSGDCYA

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below:

(SEQ ID NO: 235) METGLRWLLLVAVLKGVQCQSLEESGGDLVKPEGSLTLTCTASGFSFSSYWMCWVRQAPGKGLEWIACIVTGNGNTYYANWAKGRFTISKTSSTTVTLQM TSLTAADTATYFCAKAYDL.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:236; SEQ ID NO:237; and SEQ IDNO:238 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:234, and/or one or more of the polypeptide sequences of SEQ IDNO:239; SEQ ID NO:240; and SEQ ID NO:241 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:235, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:236; SEQ ID NO:237; and SEQ ID NO:238which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:234, and/or one or more of the polypeptide sequences of SEQ IDNO:239; SEQ ID NO:240; and SEQ ID NO:241 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:235, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:234. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:235.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:236; SEQ IDNO:237; and SEQ ID NO:238 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:234.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:239; SEQ IDNO:240; and SEQ ID NO:241 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:235.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:234; the variable heavy chain region of SEQ IDNO:235; the complementarity-determining regions (SEQ ID NO:236; SEQ IDNO:237; and SEQ ID NO:238) of the variable light chain region of SEQ IDNO:234; and the complementarity-determining regions (SEQ ID NO:239; SEQID NO:240; and SEQ ID NO:241) of the variable heavy chain region of SEQID NO:235.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb15, comprising SEQ ID NO:234 and SEQ ID NO:235, and having at leastone of the biological activities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 250) MDTRAPTQLLGLLLLWLPGSTFAAVLTQTPSPVSAAVGGTVSISCQASQSVYDNNYLSWYQQKPGQPPKLLIYGASTLASGVPSRFKGTGSGTQFTLTITDVQCDDAATYYCAGVFNDDSDDA

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below:

(SEQ ID NO: 251) METGLRWLLLVAVPKGVQCQSLEESGGRLVTPGTPLTLTCTLSGFSLSAYYMSWVRQAPGKGLEWIGFITLSDHISYARWAKGRFTISKTSTTVDLKMTSPTTEDTATYFCARSRGWGAMGRLDL.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:252; SEQ ID NO:253; and SEQ IDNO:254 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:250, and/or one or more of the polypeptide sequences of SEQ IDNO:255; SEQ ID NO:256; and SEQ ID NO:257 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:251, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:252; SEQ ID NO:253; and SEQ ID NO:254which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:250, and/or one or more of the polypeptide sequences of SEQ IDNO:255; SEQ ID NO:256; and SEQ ID NO:257 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:251, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:250. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:251.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:252; SEQ IDNO:253; and SEQ ID NO:254 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:250.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:255; SEQ IDNO:256; and SEQ ID NO:257 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:251.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:250; the variable heavy chain region of SEQ IDNO:251; the complementarity-determining regions (SEQ ID NO:252; SEQ IDNO:253; and SEQ ID NO:254) of the variable light chain region of SEQ IDNO:250; and the complementarity-determining regions (SEQ ID NO:255; SEQID NO:256; and SEQ ID NO:257) of the variable heavy chain region of SEQID NO:251.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb16, comprising SEQ ID NO:250 and SEQ ID NO:251, and having at leastone of the biological activities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 266) MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSPVSAAVGGTVTISCQASQSVYNNKNLAWYQQKSGQPPKLLIYWASTLASGVSSRFSGSGSGTQFTLTVSGVQCDDAATYYCLGVFDDDADNA

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below:

(SEQ ID NO: 267) METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTASGFSLSSYSMTWVRQAPGKGLEYIGVIGTSGSTYYATWAKGRFTISRTSTTVALKITSPTTEDTATYFCVRSLSSITFL.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:268; SEQ ID NO:269; and SEQ IDNO:270 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:266, and/or one or more of the polypeptide sequences of SEQ IDNO:271; SEQ ID NO:272; and SEQ ID NO:273 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:267, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:268; SEQ ID NO:269; and SEQ ID NO:270which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:266, and/or one or more of the polypeptide sequences of SEQ IDNO:271; SEQ ID NO:272; and SEQ ID NO:273 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:267, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:266. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:267.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:268; SEQ IDNO:269; and SEQ ID NO:270 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:266.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:271; SEQ IDNO:272; and SEQ ID NO:273 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:267.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:266; the variable heavy chain region of SEQ IDNO:267; the complementarity-determining regions (SEQ ID NO:268; SEQ IDNO:269; and SEQ ID NO:270) of the variable light chain region of SEQ IDNO:266; and the complementarity-determining regions (SEQ ID NO:271; SEQID NO:272; and SEQ ID NO:273) of the variable heavy chain region of SEQID NO:267.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb17, comprising SEQ ID NO:266 and SEQ ID NO:267, and having at leastone of the biological activities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 282) MDTRAPTQLLGLLLLWLPGARCAFELTQTPASVEAAVGGTVTINCQASQNIYRYLAWYQQKPGQPPKFLIYLASTLASGVPSRFKGSGSGTEFTLTISDL ECADAATYYCQSYYSSNSVA

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below:

(SEQ ID NO: 283) METGLRWLLLVAVLKGVQCQEQLVESGGDLVQPEGSLTLTCTASELDFSSGYWICWVRQVPGKGLEWIGCIYTGSSGSTFYASWAKGRFTISKTSSTTVTLQMTSLTAADTATYFCARGYSGFGYFKL.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:284; SEQ ID NO:285; and SEQ IDNO:286 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:282, and/or one or more of the polypeptide sequences of SEQ IDNO:287; SEQ ID NO:288; and SEQ ID NO:289 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:283, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:284; SEQ ID NO:285; and SEQ ID NO:286which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:282, and/or one or more of the polypeptide sequences of SEQ IDNO:287; SEQ ID NO:288; and SEQ ID NO:289 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:283, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:282. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:283.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:284; SEQ IDNO:285; and SEQ ID NO:286 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:282.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:287; SEQ IDNO:288; and SEQ ID NO:289 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:283.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:282; the variable heavy chain region of SEQ IDNO:283; the complementarity-determining regions (SEQ ID NO:284; SEQ IDNO:285; and SEQ ID NO:286) of the variable light chain region of SEQ IDNO:282; and the complementarity-determining regions (SEQ ID NO:287; SEQID NO:288; and SEQ ID NO:289) of the variable heavy chain region of SEQID NO:283.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb18, comprising SEQ ID NO:282 and SEQ ID NO:283, and having at leastone of the biological activities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 298) MDTRAPTQLLGLLLLWLPGARCAYDMTQTPASVEVAVGGTVTIKCQASEDIYRLLAWYQQKPGQPPKLLIYDSSDLASGVPSRFKGSGSGTEFTLAISGVQCDDAATYYCQQAWSYSDIDNA

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below:

(SEQ ID NO: 299) METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTASGFSLSSYYMSWVRQAPGKGLEWIGIITTSGNTFYASWAKGRLTISRTSTTVDLKITSPTTEDTATYFCARTSDIFYYRNL.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:300; SEQ ID NO:301; and SEQ IDNO:302 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:298, and/or one or more of the polypeptide sequences of SEQ IDNO:303; SEQ ID NO:304; and SEQ ID NO:305 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:299, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:300; SEQ ID NO:301; and SEQ ID NO:302which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:298, and/or one or more of the polypeptide sequences of SEQ IDNO:303; SEQ ID NO:304; and SEQ ID NO:305 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:299, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:298. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:299.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:300; SEQ IDNO:301; and SEQ ID NO:302 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:298.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:303; SEQ IDNO:304; and SEQ ID NO:305 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:299.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:298; the variable heavy chain region of SEQ IDNO:299; the complementarity-determining regions (SEQ ID NO:300; SEQ IDNO:301; and SEQ ID NO:302) of the variable light chain region of SEQ IDNO:298; and the complementarity-determining regions (SEQ ID NO:303; SEQID NO:304; and SEQ ID NO:305) of the variable heavy chain region of SEQID NO:299.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb19, comprising SEQ ID NO:298 and SEQ ID NO:299, and having at leastone of the biological activities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 314) MDTRAPTQLLGLLLLWLPGATFAAVLTQTASPVSAAVGATVTINCQSSQSVYNDMDLAWFQQKPGQPPKLLIYSASTLASGVPSRFSGSGSGTEFTLTISGVQCDDAATYYCLGAFDDDADNT

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below:

(SEQ ID NO: 315) METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTVSGFSLTRHAITWVRQAPGKGLEWIGCIWSGGSTYYATWAKGRFTISKTSTTVDLRITSPTTEDTATYFCARVIGDTAGYAYFTGLDL.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:316; SEQ ID NO:317; and SEQ IDNO:318 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:314, and/or one or more of the polypeptide sequences of SEQ IDNO:319; SEQ ID NO:320; and SEQ ID NO:321 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:315, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:316; SEQ ID NO:317; and SEQ ID NO:318which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:314, and/or one or more of the polypeptide sequences of SEQ IDNO:319; SEQ ID NO:320; and SEQ ID NO:321 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:315, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:314. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:315.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:316; SEQ IDNO:317; and SEQ ID NO:318 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:314.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:319; SEQ IDNO:320; and SEQ ID NO:321 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:315.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:314; the variable heavy chain region of SEQ IDNO:315; the complementarity-determining regions (SEQ ID NO:316; SEQ IDNO:317; and SEQ ID NO:318) of the variable light chain region of SEQ IDNO:314; and the complementarity-determining regions (SEQ ID NO:319; SEQID NO:320; and SEQ ID NO:321) of the variable heavy chain region of SEQID NO:315.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb20, comprising SEQ ID NO:314 and SEQ ID NO:315, and having at leastone of the biological activities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 330) MDTRAPTQLLGLLLLWLPGARCAYDMTQTPASVEVAVGGTVTIKCQASQSVYNWLSWYQQKPGQPPKLLIYTASSLASGVPSRFSGSGSGTEFTLTISGV ECADAATYYCQQGYTSDVDNV

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below:

(SEQ ID NO: 331) METGLRWLLLVAVLKGVQCQSLEEAGGRLVTPGTPLTLTCTVSGIDLSSYAMGWVRQAPGKGLEYIGIISSSGSTYYATWAKGRFTISQASSTTVDLKITSPTTEDSATYFCARGGAGSGGVWLLDGFDP.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:332; SEQ ID NO:333; and SEQ IDNO:334 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:330, and/or one or more of the polypeptide sequences of SEQ IDNO:335; SEQ ID NO:336; and SEQ ID NO:337 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:331, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:332; SEQ ID NO:333; and SEQ ID NO:334which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:330, and/or one or more of the polypeptide sequences of SEQ IDNO:335; SEQ ID NO:336; and SEQ ID NO:337 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:331, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:330. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:331.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:332; SEQ IDNO:333; and SEQ ID NO:334 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:330.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:335; SEQ IDNO:336; and SEQ ID NO:337 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:331.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:330; the variable heavy chain region of SEQ IDNO:331; the complementarity-determining regions (SEQ ID NO:332; SEQ IDNO:333; and SEQ ID NO:334) of the variable light chain region of SEQ IDNO:330; and the complementarity-determining regions (SEQ ID NO:335; SEQID NO:336; and SEQ ID NO:337) of the variable heavy chain region of SEQID NO:331.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb21, comprising SEQ ID NO:330 and SEQ ID NO:331, and having at leastone of the biological activities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 346) MDTRAPTQLLGLLLLWLPGAKCADVVMTQTPASVSAAVGGTVTINCQASENIYNWLAWYQQKPGQPPKLLIYTVGDLASGVSSRFKGSGSGTEFTLTISDLECADAATYYCQQGYSSSYVDNV

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below:

(SEQ ID NO: 347) METGLRWLLLVAVLKGVQCQEQLKESGGRLVTPGTPLTLTCTVSGFSLNDYAVGWFRQAPGKGLEWIGYIRSSGTTAYATWAKGRFTISATSTTVDLKITSPTTEDTATYFCARGGAGSSGVWILDGFAP.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:348; SEQ ID NO:349; and SEQ IDNO:350 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:346, and/or one or more of the polypeptide sequences of SEQ IDNO:351; SEQ ID NO:352; and SEQ ID NO:353 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:347, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:348; SEQ ID NO:349; and SEQ ID NO:350which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:346, and/or one or more of the polypeptide sequences of SEQ IDNO:351; SEQ ID NO:352; and SEQ ID NO:353 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:347, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:346. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:347.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:348; SEQ IDNO:349; and SEQ ID NO:350 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:346.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:351; SEQ IDNO:352; and SEQ ID NO:353 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:347.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:346; the variable heavy chain region of SEQ IDNO:347; the complementarity-determining regions (SEQ ID NO:348; SEQ IDNO:349; and SEQ ID NO:350) of the variable light chain region of SEQ IDNO:346; and the complementarity-determining regions (SEQ ID NO:351; SEQID NO:352; and SEQ ID NO:353) of the variable heavy chain region of SEQID NO:347.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb22, comprising SEQ ID NO:346 and SEQ ID NO:347, and having at leastone of the biological activities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 362) MDTRAPTQLLGLLLLWLPGATFAQVLTQTPSSVSAAVGGTVTINCQASQSVYQNNYLSWFQQKPGQPPKLLIYGAATLASGVPSRFKGSGSGTQFTLTIS DLECDDAATYYCAGAYRDVDS

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below:

(SEQ ID NO: 363) METGLRWLLLVAVLKGVQCQSLEESGGDLVKPGASLTLTCTASGFSFTSTYYIYWVRQAPGKGLEWIACIDAGSSGSTYYATWVNGRFTISKTSSTTVTLQMTSLTAADTATYFCAKWDYGGNVGWGYDL.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:364; SEQ ID NO:365; and SEQ IDNO:366 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:362, and/or one or more of the polypeptide sequences of SEQ IDNO:367; SEQ ID NO:368; and SEQ ID NO:369 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:363, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:364; SEQ ID NO:365; and SEQ ID NO:366which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:362, and/or one or more of the polypeptide sequences of SEQ IDNO:367; SEQ ID NO:368; and SEQ ID NO:369 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:363, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:362. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:363.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:364; SEQ IDNO:365; and SEQ ID NO:366 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:362.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:367; SEQ IDNO:368; and SEQ ID NO:369 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:363.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:362; the variable heavy chain region of SEQ IDNO:363; the complementarity-determining regions (SEQ ID NO:364; SEQ IDNO:365; and SEQ ID NO:366) of the variable light chain region of SEQ IDNO:362; and the complementarity-determining regions (SEQ ID NO:367; SEQID NO:368; and SEQ ID NO:369) of the variable heavy chain region of SEQID NO:363.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb23, comprising SEQ ID NO:362 and SEQ ID NO:363, and having at leastone of the biological activities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 378) MDTRAPTQLLGLLLLWLPGARCAFELTQTPSSVEAAVGGTVTIKCQASQSISSYLAWYQQKPGQPPKFLIYRASTLASGVPSRFKGSGSGTEFTLTISDL ECADAATYYCQSYYDSVSNP

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below:

(SEQ ID NO: 379) METGLRWLLLVAVLKGVQCQSLEESGGDLVKPEGSLTLTCKASGLDLGTYWFMCWVRQAPGKGLEWIACIYTGSSGSTFYASWVNGRFTISKTSSTTVTLQMTSLTAADTATYFCARGYSGYGYFKL.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:380; SEQ ID NO:381; and SEQ IDNO:382 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:378, and/or one or more of the polypeptide sequences of SEQ IDNO:383; SEQ ID NO:384; and SEQ ID NO:385 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:379, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:380; SEQ ID NO:381; and SEQ ID NO:382which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:378, and/or one or more of the polypeptide sequences of SEQ IDNO:383; SEQ ID NO:384; and SEQ ID NO:385 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:379, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:378. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:379.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:380; SEQ IDNO:381; and SEQ ID NO:382 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:378.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:383; SEQ IDNO:384; and SEQ ID NO:385 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:379.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:378; the variable heavy chain region of SEQ IDNO:379; the complementarity-determining regions (SEQ ID NO:380; SEQ IDNO:381; and SEQ ID NO:382) of the variable light chain region of SEQ IDNO:378; and the complementarity-determining regions (SEQ ID NO:383; SEQID NO:384; and SEQ ID NO:385) of the variable heavy chain region of SEQID NO:379.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb24, comprising SEQ ID NO:378 and SEQ ID NO:379, and having at leastone of the biological activities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 394) MDTRAPTQLLGLLLLWLPGVTFAIEMTQSPFSVSAAVGGTVSISCQASQSVYKNNQLSWYQQKSGQPPKLLIYGASALASGVPSRFKGSGSGTEFTLTISDVQCDDAATYYCAGAITGSIDTDG

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below:

(SEQ ID NO: 395) METGLRWLLLVAVLKGVQCQSLEESGGDLVKPGASLTLTCTTSGFSFSSSYFICWVRQAPGKGLEWIACIYGGDGSTYYASWAKGRFTISKTSSTTVTLQMTSLTAADTATYFCAREWAYSQGYFGAFDL.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:396; SEQ ID NO:397; and SEQ IDNO:398 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:394, and/or one or more of the polypeptide sequences of SEQ IDNO:399; SEQ ID NO:400; and SEQ ID NO:401 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:395, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:396; SEQ ID NO:397; and SEQ ID NO:398which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:394, and/or one or more of the polypeptide sequences of SEQ IDNO:399; SEQ ID NO:400; and SEQ ID NO:401 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:395, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:394. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:395.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:396; SEQ IDNO:397; and SEQ ID NO:398 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:394.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:399; SEQ IDNO:400; and SEQ ID NO:401 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:395.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:394; the variable heavy chain region of SEQ IDNO:395; the complementarity-determining regions (SEQ ID NO:396; SEQ IDNO:397; and SEQ ID NO:398) of the variable light chain region of SEQ IDNO:394; and the complementarity-determining regions (SEQ ID NO:399; SEQID NO:400; and SEQ ID NO:401) of the variable heavy chain region of SEQID NO:395.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb25, comprising SEQ ID NO:394 and SEQ ID NO:395, and having at leastone of the biological activities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 410) MDTRAPTQLLGLLLLWLPGARCDVVMTQTPASVEAAVGGTVTIKCQASEDISSYLAWYQQKPGQPPKLLIYAASNLESGVSSRFKGSGSGTEYTLTISDLECADAATYYCQCTYGTISISDGNA

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below:

(SEQ ID NO: 411) METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTVSGFSLSSYFMTWVRQAPGEGLEYIGFINPGGSAYYASWVKGRFTISKSSTTVDLKITSPTTEDTATYFCARVLIVSYGAFTI.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:412; SEQ ID NO:413; and SEQ IDNO:414 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:410, and/or one or more of the polypeptide sequences of SEQ IDNO:415; SEQ ID NO:416; and SEQ ID NO:417 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:411, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:412; SEQ ID NO:413; and SEQ ID NO:414which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:410, and/or one or more of the polypeptide sequences of SEQ IDNO:415; SEQ ID NO:416; and SEQ ID NO:417 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:411, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:410. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:411.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:412; SEQ IDNO:413; and SEQ ID NO:414 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:410.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:415; SEQ IDNO:416; and SEQ ID NO:417 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:411.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:410; the variable heavy chain region of SEQ IDNO:411; the complementarity-determining regions (SEQ ID NO:412; SEQ IDNO:413; and SEQ ID NO:414) of the variable light chain region of SEQ IDNO:410; and the complementarity-determining regions (SEQ ID NO:415; SEQID NO:416; and SEQ ID NO:417) of the variable heavy chain region of SEQID NO:411.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb26, comprising SEQ ID NO:410 and SEQ ID NO:411, and having at leastone of the biological activities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 426) MDTRAPTQLLGLLLLWLPGARCDVVMTQTPASVSAAVGGTVTIKCQASEDIESYLAWYQQKPGQPPKLLIYGASNLESGVSSRFKGSGSGTEFTLTISDLECADAATYYCQCTYGIISISDGNA

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below:

(SEQ ID NO: 427) METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTVSGFSLSSYFMTWVRQAPGEGLEYIGFMNTGDNAYYASWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARVLVVAYGAFNI.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:428; SEQ ID NO:429; and SEQ IDNO:430 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:426, and/or one or more of the polypeptide sequences of SEQ IDNO:431; SEQ ID NO:432; and SEQ ID NO:433 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:427, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:428; SEQ ID NO:429; and SEQ ID NO:430which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:426, and/or one or more of the polypeptide sequences of SEQ IDNO:431; SEQ ID NO:432; and SEQ ID NO:433 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:427, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:426. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:427.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:428; SEQ IDNO:429; and SEQ ID NO:430 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:426.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:431; SEQ IDNO:432; and SEQ ID NO:433 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:427.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:426; the variable heavy chain region of SEQ IDNO:427; the complementarity-determining regions (SEQ ID NO:428; SEQ IDNO:429; and SEQ ID NO:430) of the variable light chain region of SEQ IDNO:426; and the complementarity-determining regions (SEQ ID NO:431; SEQID NO:432; and SEQ ID NO:433) of the variable heavy chain region of SEQID NO:427.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb27, comprising SEQ ID NO:426 and SEQ ID NO:427, and having at leastone of the biological activities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 442) MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSPVSEPVGGTVSISCQSSKSVMNNNYLAWYQQKPGQPPKLLIYGASNLASGVPSRFSGSGSGTQFTLTISDVQCDDAATYYCQGGYTGYSDHGT

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below:

(SEQ ID NO: 443) METGLRWLLLVAVLKGVQCQSVEESGGRLVKPDETLTLTCTVSGIDLSSYPMNWVRQAPGKGLEWIGFINTGGTIVYASWAKGRFTISKTSTTVDLKMTSPTTEDTATYFCARGSYVSSGYAYYFNV.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:444; SEQ ID NO:445; and SEQ IDNO:446 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:442, and/or one or more of the polypeptide sequences of SEQ IDNO:447; SEQ ID NO:448; and SEQ ID NO:449 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:443, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:444; SEQ ID NO:445; and SEQ ID NO:446which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:442, and/or one or more of the polypeptide sequences of SEQ IDNO:447; SEQ ID NO:448; and SEQ ID NO:449 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:443, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:442. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:443.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:444; SEQ IDNO:445; and SEQ ID NO:446 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:442.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:447; SEQ IDNO:448; and SEQ ID NO:449 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:443.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:442; the variable heavy chain region of SEQ IDNO:443; the complementarity-determining regions (SEQ ID NO:444; SEQ IDNO:445; and SEQ ID NO:446) of the variable light chain region of SEQ IDNO:442; and the complementarity-determining regions (SEQ ID NO:447; SEQID NO:448; and SEQ ID NO:449) of the variable heavy chain region of SEQID NO:443.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb28, comprising SEQ ID NO:442 and SEQ ID NO:443, and having at leastone of the biological activities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 458) MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSPVSAAVGGTVSISCQSSQSVYNNNWLSWFQQKPGQPPKLLIYKASTLASGVPSRFKGSGSGTQFTLTIS DVQCDDVATYYCAGGYLDSVI

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below:

(SEQ ID NO: 459) METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTVSGFSLSTYSINWVRQAPGKGLEWIGIIANSGTTFYANWAKGRFTVSKTSTTVDLKITSPTTEDTATYFCARESGMYNEYGKFNI.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:460; SEQ ID NO:461; and SEQ IDNO:462 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:458, and/or one or more of the polypeptide sequences of SEQ IDNO:463; SEQ ID NO:464; and SEQ ID NO:465 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:459, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:460; SEQ ID NO:461; and SEQ ID NO:462which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:458, and/or one or more of the polypeptide sequences of SEQ IDNO:463; SEQ ID NO:464; and SEQ ID NO:465 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:459, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:458. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:459.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:460; SEQ IDNO:461; and SEQ ID NO:462 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:458.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:463; SEQ IDNO:464; and SEQ ID NO:465 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:459.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:458; the variable heavy chain region of SEQ IDNO:459; the complementarity-determining regions (SEQ ID NO:460; SEQ IDNO:461; and SEQ ID NO:462) of the variable light chain region of SEQ IDNO:458; and the complementarity-determining regions (SEQ ID NO:463; SEQID NO:464; and SEQ ID NO:465) of the variable heavy chain region of SEQID NO:459.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb29, comprising SEQ ID NO:458 and SEQ ID NO:459, and having at leastone of the biological activities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 474) MDTRAPTQLLGLLLLWLPGARCASDMTQTPSSVSAAVGGTVTINCQASENIYSFLAWYQQKPGQPPKLLIFKASTLASGVSSRFKGSGSGTQFTLTISDLECDDAATYYCQQGATVYDIDNN

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below:

(SEQ ID NO: 475) METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTVSGIDLSAYAMIWVRQAPGEGLEWITIIYPNGITYYANWAKGRFTVSKTSTAMDLKITSPTTEDTATYFCARDAESSKNAYWGYFNV.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:476; SEQ ID NO:477; and SEQ IDNO:478 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:474, and/or one or more of the polypeptide sequences of SEQ IDNO:479; SEQ ID NO:480; and SEQ ID NO:481 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:475, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:476; SEQ ID NO:477; and SEQ ID NO:478which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:474, and/or one or more of the polypeptide sequences of SEQ IDNO:479; SEQ ID NO:480; and SEQ ID NO:481 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:475, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention specificity to IL-6. In one embodiment ofthe invention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:474. Inanother embodiment of the invention, antibody fragments of the inventioncomprise, or alternatively consist of, the polypeptide sequence of SEQID NO:475.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:476; SEQ IDNO:477; and SEQ ID NO:478 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:474.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:479; SEQ IDNO:480; and SEQ ID NO:481 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:475.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:474; the variable heavy chain region of SEQ IDNO:475; the complementarity-determining regions (SEQ ID NO:476; SEQ IDNO:477; and SEQ ID NO:478) of the variable light chain region of SEQ IDNO:474; and the complementarity-determining regions (SEQ ID NO:479; SEQID NO:480; and SEQ ID NO:481) of the variable heavy chain region of SEQID NO:475.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb30, comprising SEQ ID NO:474 and SEQ ID NO:475, and having at leastone of the biological activities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 490) MDTRAPTQLLGLLLLWLPGARCASDMTQTPSSVSAAVGGTVTINCQASENIYSFLAWYQQKPGQPPKLLIFRASTLASGVSSRFKGSGSGTQFTLTISDLECDDAATYYCQQGATVYDIDNN

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below:

(SEQ ID NO: 491) METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTVSGIDLSAYAMIWVRQAPGEGLEWITHYPNGITYYANWAKGRFTVSKTSTAMDLKITSPTTEDTATYFCARDAESSKNAYWGYFNV.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:492; SEQ ID NO:493; and SEQ IDNO:494 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:490, and/or one or more of the polypeptide sequences of SEQ IDNO:495; SEQ ID NO:496; and SEQ ID NO:497 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:491, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:492; SEQ ID NO:493; and SEQ ID NO:494which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:490, and/or one or more of the polypeptide sequences of SEQ IDNO:495; SEQ ID NO:496; and SEQ ID NO:497 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:491, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:490. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:491.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:492; SEQ IDNO:493; and SEQ ID NO:494 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:490.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:495; SEQ IDNO:496; and SEQ ID NO:497 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:491.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:490; the variable heavy chain region of SEQ IDNO:491; the complementarity-determining regions (SEQ ID NO:492; SEQ IDNO:493; and SEQ ID NO:494) of the variable light chain region of SEQ IDNO:490; and the complementarity-determining regions (SEQ ID NO:495; SEQID NO:496; and SEQ ID NO:497) of the variable heavy chain region of SEQID NO:491.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb31, comprising SEQ ID NO:490 and SEQ ID NO:491, and having at leastone of the biological activities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 506) MDTRAPTQLLGLLLLWLPGATFAIEMTQTPSPVSAAVGGTVTINCQASESVFNNMLSWYQQKPGHSPKLLIYDASDLASGVPSRFKGSGSGTQFTLTISGVECDDAATYYCAGYKSDSNDGDNV

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below:

(SEQ ID NO: 507) METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTVSGFSLNRNSITWVRQAPGEGLEWIGIITGSGRTYYANWAKGRFTISKTSTTVDLKMTSPTTEDTATYFCARGHPGLGSGNI.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:508; SEQ ID NO:509; and SEQ IDNO:510 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:506, and/or one or more of the polypeptide sequences of SEQ IDNO:511; SEQ ID NO:512; and SEQ ID NO:513 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:507, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:508; SEQ ID NO:509; and SEQ ID NO:510which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:506, and/or one or more of the polypeptide sequences of SEQ IDNO:511; SEQ ID NO:512; and SEQ ID NO:513 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:507, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:506. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:507.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:508; SEQ IDNO:509; and SEQ ID NO:510 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:506.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:511; SEQ IDNO:512; and SEQ ID NO:513 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:507.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:506; the variable heavy chain region of SEQ IDNO:507; the complementarity-determining regions (SEQ ID NO:508; SEQ IDNO:509; and SEQ ID NO:510) of the variable light chain region of SEQ IDNO:506; and the complementarity-determining regions (SEQ ID NO:511; SEQID NO:512; and SEQ ID NO:513) of the variable heavy chain region of SEQID NO:507.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb32, comprising SEQ ID NO:506 and SEQ ID NO:507, and having at leastone of the biological activities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 522) MDTRAPTQLLGLLLLWLPGATFAQVLTQTASSVSAAVGGTVTINCQSSQSVYNNYLSWYQQKPGQPPKLLIYTASSLASGVPSRFKGSGSGTQFTLTISEVQCDDAATYYCQGYYSGPIIT

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below:

(SEQ ID NO: 523) METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTASGFSLNNYYIQWVRQAPGEGLEWIGIIYAGGSAYYATWANGRFTIAKTSSTTVDLKMTSLTTEDTATYFCARGTFDGYEL.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:524; SEQ ID NO:525; and SEQ IDNO:526 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:522, and/or one or more of the polypeptide sequences of SEQ IDNO:527; SEQ ID NO:528; and SEQ ID NO:529 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:523, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:524; SEQ ID NO:525; and SEQ ID NO:526which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:522, and/or one or more of the polypeptide sequences of SEQ IDNO:527; SEQ ID NO:528; and SEQ ID NO:529 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:523, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:522. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:523.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:524; SEQ IDNO:525; and SEQ ID NO:526 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:522.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:527; SEQ IDNO:528; and SEQ ID NO:529 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:523.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:522; the variable heavy chain region of SEQ IDNO:523; the complementarity-determining regions (SEQ ID NO:524; SEQ IDNO:525; and SEQ ID NO:526) of the variable light chain region of SEQ IDNO:522; and the complementarity-determining regions (SEQ ID NO:527; SEQID NO:528; and SEQ ID NO:529) of the variable heavy chain region of SEQID NO:523.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb33, comprising SEQ ID NO:522 and SEQ ID NO:523, and having at leastone of the biological activities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 538) MDTRAPTQLLGLLLLWLPGATFAQVLTQTPSPVSVPVGDTVTISCQSSESVYSNNLLSWYQQKPGQPPKLLIYRASNLASGVPSRFKGSGSGTQFTLTISGAQCDDAATYYCQGYYSGVINS

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below:

(SEQ ID NO: 539) METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTVSGFSLSSYFMSWVRQAPGEGLEYIGFINPGGSAYYASWASGRLTISKTSTTVDLKITSPTTEDTATYFCARILIVSYGAFTI.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:540; SEQ ID NO:541; and SEQ IDNO:542 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:538, and/or one or more of the polypeptide sequences of SEQ IDNO:543; SEQ ID NO:544; and SEQ ID NO:545 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:539, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:540; SEQ ID NO:541; and SEQ ID NO:542which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:538, and/or one or more of the polypeptide sequences of SEQ IDNO:543; SEQ ID NO:544; and SEQ ID NO:545 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:539, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention specificity to IL-6. In one embodiment ofthe invention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:538. Inanother embodiment of the invention, antibody fragments of the inventioncomprise, or alternatively consist of, the polypeptide sequence of SEQID NO:539.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:540; SEQ IDNO:541; and SEQ ID NO:542 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:538.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:543; SEQ IDNO:544; and SEQ ID NO:545 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:539.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:538; the variable heavy chain region of SEQ IDNO:539; the complementarity-determining regions (SEQ ID NO:540; SEQ IDNO:541; and SEQ ID NO:542) of the variable light chain region of SEQ IDNO:538; and the complementarity-determining regions (SEQ ID NO:543; SEQID NO:544; and SEQ ID NO:545) of the variable heavy chain region of SEQID NO:539.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb34, comprising SEQ ID NO:538 and SEQ ID NO:539, and having at leastone of the biological activities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 554) MDTRAPTQLLGLLLLWLPGARCAYDMTQTPASVEVAVGGTVTIKCQATESIGNELSWYQQKPGQAPKLLIYSASTLASGVPSRFKGSGSGTQFTLTITGVECDDAATYYCQQGYSSANIDNA

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below:

(SEQ ID NO: 555) METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTVSGFSLSKYYMSWVRQAPEKGLKYIGYIDSTTVNTYYATWARGRFTISKTSTTVDLKITSPTSEDTATYFCARGSTYFTDGGHRLDL.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:556; SEQ ID NO:557; and SEQ IDNO:558 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:554, and/or one or more of the polypeptide sequences of SEQ IDNO:559; SEQ ID NO:560; and SEQ ID NO:561 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:555, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:556; SEQ ID NO:557; and SEQ ID NO:558which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:554, and/or one or more of the polypeptide sequences of SEQ IDNO:559; SEQ ID NO:560; and SEQ ID NO:561 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:555, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:554. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:555.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:556; SEQ IDNO:557; and SEQ ID NO:558 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:554.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:559; SEQ IDNO:560; and SEQ ID NO:561 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:555.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:554; the variable heavy chain region of SEQ IDNO:555; the complementarity-determining regions (SEQ ID NO:556; SEQ IDNO:557; and SEQ ID NO:558) of the variable light chain region of SEQ IDNO:554; and the complementarity-determining regions (SEQ ID NO:559; SEQID NO:560; and SEQ ID NO:561) of the variable heavy chain region of SEQID NO:555.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb35, comprising SEQ ID NO:554 and SEQ ID NO:555, and having at leastone of the biological activities set forth herein.

In another embodiment, the invention includes antibodies having bindingspecificity to IL-6 and possessing a variable light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 570) MDTRAPTQLLGLLLLWLPGARCAYDMTQTPASVEVAVGGTVTIKCQATESIGNELSWYQQKPGQAPKLLIYSASTLASGVPSRFKGSGSGTQFTLTITGVECDDAATYYCQQGYSSANIDNA

The invention also includes antibodies having binding specificity toIL-6 and possessing a variable heavy chain sequence comprising thesequence set forth below:

(SEQ ID NO: 571) METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTVSGFSLSTYNMGWVRQAPGKGLEWIGSITIDGRTYYASWAKGRFTVSKSSTTVDLKMTSLTTGDTATYFCARILIVSYGAFTI.

The invention further contemplates antibodies comprising one or more ofthe polypeptide sequences of SEQ ID NO:572; SEQ ID NO:573; and SEQ IDNO:574 which correspond to the complementarity-determining regions(CDRs, or hypervariable regions) of the variable light chain sequence ofSEQ ID NO:570, and/or one or more of the polypeptide sequences of SEQ IDNO:575; SEQ ID NO:576; and SEQ ID NO:577 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:571, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

In another embodiment, the invention contemplates other antibodies, suchas for example chimeric antibodies, comprising one or more of thepolypeptide sequences of SEQ ID NO:572; SEQ ID NO:573; and SEQ ID NO:574which correspond to the complementarity-determining regions (CDRs, orhypervariable regions) of the variable light chain sequence of SEQ IDNO:570, and/or one or more of the polypeptide sequences of SEQ IDNO:575; SEQ ID NO:576; and SEQ ID NO:577 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:571, or combinations ofthese polypeptide sequences. In another embodiment of the invention, theantibodies of the invention include combinations of the CDRs and thevariable heavy and light chain sequences set forth above.

The invention also contemplates fragments of the antibody having bindingspecificity to IL-6. In one embodiment of the invention, antibodyfragments of the invention comprise, or alternatively consist of, thepolypeptide sequence of SEQ ID NO:570. In another embodiment of theinvention, antibody fragments of the invention comprise, oralternatively consist of, the polypeptide sequence of SEQ ID NO:571.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:572; SEQ IDNO:573; and SEQ ID NO:574 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable light chain sequence of SEQ ID NO:570.

In a further embodiment of the invention, fragments of the antibodyhaving binding specificity to IL-6 comprise, or alternatively consistof, one or more of the polypeptide sequences of SEQ ID NO:575; SEQ IDNO:576; and SEQ ID NO:577 which correspond to thecomplementarity-determining regions (CDRs, or hypervariable regions) ofthe variable heavy chain sequence of SEQ ID NO:571.

The invention also contemplates antibody fragments which include one ormore of the antibody fragments described herein. In one embodiment ofthe invention, fragments of the antibodies having binding specificity toIL-6 comprise, or alternatively consist of, one, two, three or more,including all of the following antibody fragments: the variable lightchain region of SEQ ID NO:570; the variable heavy chain region of SEQ IDNO:571; the complementarity-determining regions (SEQ ID NO:572; SEQ IDNO:573; and SEQ ID NO:574) of the variable light chain region of SEQ IDNO:570; and the complementarity-determining regions (SEQ ID NO:575; SEQID NO:576; and SEQ ID NO:577) of the variable heavy chain region of SEQID NO:571.

In a preferred embodiment of the invention, the anti-IL-6 antibody isAb36, comprising SEQ ID NO:570 and SEQ ID NO:571, and having at leastone of the biological activities set forth herein.

Such antibody fragments may be present in one or more of the followingnon-limiting forms: Fab, Fab′, F(ab′)₂, Fv and single chain Fv antibodyforms. In a preferred embodiment, the anti-IL-6 antibodies describedherein further comprises the kappa constant light chain sequencecomprising the sequence set forth below:

(SEQ ID NO: 586) VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTK SFNRGEC.

In another preferred embodiment, the anti-IL-6 antibodies describedherein further comprises and the gamma-1 constant heavy chainpolypeptide sequence comprising the sequence set forth below:

(SEQ ID NO: 588) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.

In another embodiment, the invention contemplates an isolated anti-IL-6antibody comprising a V_(H) polypeptide sequence selected from the groupconsisting of: SEQ ID NO:3, 18, 19, 665, 22, 668, 37, 672, 54, 676, 70,680, 86, 684, 102, 688, 117, 118, 692 123, 139, 155, 171, 187, 203, 219,235, 251, 267, 283, 299, 315, 331, 347, 363, 379, 395, 411, 427, 443,459, 475, 491, 507, 523, 539, 555 and SEQ ID NO:571 or those containedin SEQ ID NO:652, 653, 654, 655, 656 or 657; and further comprising aV_(L) polypeptide sequence selected from the group consisting of: SEQ IDNO:2, 651, 709, 20, 667, 37, 671, 53, 675, 69, 679, 85, 683, 101, 687,119, 693, 122, 138, 154, 170, 186, 202, 218, 234, 250, 266, 282, 298,314, 330, 346, 362, 378, 394, 410, 426, 442, 458, 474, 490, 506, 522,538, 554 and SEQ ID NO:570 or in SEQ ID NO:647, 648, 649, 650 or 651 ora variant thereof wherein one or more of the framework residues (FRresidues) or CDR residues in said V_(H or) V_(L) polypeptide has beensubstituted with another amino acid residue resulting in an anti-IL-6antibody that specifically binds IL-6. The invention contemplateshumanized and chimeric forms of these antibodies. The chimericantibodies may include an Fc derived from IgG1, IgG2, IgG3, IgG4, IgG5,IgG6, IgG7, IgG8, IgG9, IgG10, IgG11, IgG12, IgG13, IgG14, IgG15, IgG16,IgG17, IgG18 or IgG19 constant regions.

In one embodiment of the invention, the antibodies or V_(H) or V_(L)polypeptides originate or are selected from one or more rabbit B cellpopulations prior to initiation of the humanization process referencedherein.

In another embodiment of the invention, the anti-IL-6 antibodies andfragments thereof have binding specificity for primate homologs of thehuman IL-6 protein. Non-limiting examples of primate homologs of thehuman IL-6 protein are IL-6 obtained from Macaca fascicularis (alsoknown as the cynomolgus monkey) and the Rhesus monkey. In anotherembodiment of the invention, the anti-IL-6 antibodies and fragmentsthereof inhibits the association of IL-6 with IL-6R, and/or theproduction of IL-6/IL-6R/gp130 complexes and/or the production ofIL-6/IL-6R/gp130 multimers and/or antagonizes the biological effects ofone or more of the foregoing.

As stated previously herein, antibodies and fragments thereof may bemodified post-translationally to add effector moieties such as chemicallinkers, detectable moieties such as for example fluorescent dyes,enzymes, substrates, bioluminescent materials, radioactive materials,and chemiluminescent moieties, or functional moieties such as forexample streptavidin, avidin, biotin, a cytotoxin, a cytotoxic agent,and radioactive materials.

Regarding detectable moieties, further exemplary enzymes include, butare not limited to, horseradish peroxidase, acetylcholinesterase,alkaline phosphatase, beta-galactosidase and luciferase. Furtherexemplary fluorescent materials include, but are not limited to,rhodamine, fluorescein, fluorescein isothiocyanate, umbelliferone,dichlorotriazinylamine, phycoerythrin and dansyl chloride. Furtherexemplary chemiluminescent moieties include, but are not limited to,luminol. Further exemplary bioluminescent materials include, but are notlimited to, luciferin and aequorin. Further exemplary radioactivematerials include, but are not limited to, Iodine 125 (¹²⁵I), Carbon 14(¹⁴C), Sulfur 35 (³⁵S), Tritium (³H) and Phosphorus 32 (³²P).

Regarding functional moieties, exemplary cytotoxic agents include, butare not limited to, methotrexate, aminopterin, 6-mercaptopurine,6-thioguanine, cytarabine, 5-fluorouracil decarbazine; alkylating agentssuch as mechlorethamine, thioepa chlorambucil, melphalan, carmustine(BSNU), mitomycin C, lomustine (CCNU), 1-methylnitrosourea,cyclothosphamide, mechlorethamine, busulfan, dibromomannitol,streptozotocin, mitomycin C, cis-dichlorodiamine platinum (II) (DDP)cisplatin and carboplatin (paraplatin); anthracyclines includedaunorubicin (formerly daunomycin), doxorubicin (adriamycin),detorubicin, carminomycin, idarubicin, epirubicin, mitoxantrone andbisantrene; antibiotics include dactinomycin (actinomycin D), bleomycin,calicheamicin, mithramycin, and anthramycin (AMC); and antimytoticagents such as the vinca alkaloids, vincristine and vinblastine. Othercytotoxic agents include paclitaxel (taxol), ricin, pseudomonasexotoxin, gemcitabine, cytochalasin B, gramicidin D, ethidium bromide,emetine, etoposide, tenoposide, colchicin, dihydroxy anthracin dione,1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine,propranolol, puromycin, procarbazine, hydroxyurea, asparaginase,corticosteroids, mytotane (O,P′-(DDD)), interferons, and mixtures ofthese cytotoxic agents.

Further cytotoxic agents include, but are not limited to,chemotherapeutic agents such as carboplatin, cisplatin, paclitaxel,gemcitabine, calicheamicin, doxorubicin, 5-fluorouracil, mitomycin C,actinomycin D, cyclophosphamide, vincristine and bleomycin. Toxicenzymes from plants and bacteria such as ricin, diphtheria toxin andPseudomonas toxin may be conjugated to the humanized antibodies, orbinding fragments thereof, to generate cell-type-specific-killingreagents (Youle, et al., Proc. Nat'l Acad. Sci. USA 77:5483 (1980);Gilliland, et al., Proc. Nat'l Acad. Sci. USA 77:4539 (1980); Krolick,et al., Proc. Nat'l Acad. Sci. USA 77:5419 (1980)).

Other cytotoxic agents include cytotoxic ribonucleases as described byGoldenberg in U.S. Pat. No. 6,653,104. Embodiments of the invention alsorelate to radioimmunoconjugates where a radionuclide that emits alpha orbeta particles is stably coupled to the antibody, or binding fragmentsthereof, with or without the use of a complex-forming agent. Suchradionuclides include beta-emitters such as Phosphorus-32 (³²P),Scandium-47 (⁴⁷Sc), Copper-67 (⁶⁷Cu), Gallium-67 (⁶⁷Ga), Yttrium-88(⁸⁸Y), Yttrium-90 (⁹⁰Y), Iodine-125 (¹²⁵I), Iodine-131 (¹³¹I),Samarium-153 (¹⁵³SM), Lutetium-177 (¹⁷⁷Lu), Rhenium-186 (¹⁸⁶Re) orRhenium-188 (¹⁸⁸Re), and alpha-emitters such as Astatine-211 (²¹¹At),Lead-212 (²¹²Pb), Bismuth-212 (²¹²Bi) or -213 (²¹³Bi) or Actinium-225(²²⁵Ac).

Methods are known in the art for conjugating an antibody or bindingfragment thereof to a detectable moiety and the like, such as forexample those methods described by Hunter et al, Nature 144:945 (1962);David et al, Biochemistry 13:1014 (1974); Pain et al, J. Immunol. Meth.40:219 (1981); and Nygren, J., Histochem. and Cytochem. 30:407 (1982).

Embodiments described herein further include variants and equivalentsthat are substantially homologous to the antibodies, antibody fragments,diabodies, SMIPs, camelbodies, nanobodies, IgNAR, polypeptides, variableregions and CDRs set forth herein. These may contain, e.g., conservativesubstitution mutations, (i.e., the substitution of one or more aminoacids by similar amino acids). For example, conservative substitutionrefers to the substitution of an amino acid with another within the samegeneral class, e.g., one acidic amino acid with another acidic aminoacid, one basic amino acid with another basic amino acid, or one neutralamino acid by another neutral amino acid. What is intended by aconservative amino acid substitution is well known in the art.

In another embodiment, the invention contemplates polypeptide sequenceshaving at least 90% or greater sequence homology to any one or more ofthe polypeptide sequences of antibody fragments, variable regions andCDRs set forth herein. More preferably, the invention contemplatespolypeptide sequences having at least 95% or greater sequence homology,even more preferably at least 98% or greater sequence homology, andstill more preferably at least 99% or greater sequence homology to anyone or more of the polypeptide sequences of antibody fragments, variableregions and CDRs set forth herein. Methods for determining homologybetween nucleic acid and amino acid sequences are well known to those ofordinary skill in the art.

In another embodiment, the invention further contemplates theabove-recited polypeptide homologs of the antibody fragments, variableregions and CDRs set forth herein further having anti-IL-6 activity.Non-limiting examples of anti-IL-6 activity are set forth herein.

In another embodiment, the invention further contemplates the generationand use of anti-idiotypic antibodies that bind any of the foregoingsequences. In an exemplary embodiment, such an anti-idiotypic antibodycould be administered to a subject who has received an anti-IL-6antibody to modulate, reduce, or neutralize, the effect of the anti-IL-6antibody. Such anti-idiotypic antibodies could also be useful fortreatment of an autoimmune disease characterized by the presence ofanti-IL-6 antibodies. A further exemplary use of such anti-idiotypicantibodies is for detection of the anti-IL-6 antibodies of the presentinvention, for example to monitor the levels of the anti-IL-6 antibodiespresent in a subject's blood or other bodily fluids.

The present invention also contemplates anti-IL-6 antibodies comprisingany of the polypeptide or polynucleotide sequences described hereinsubstituted for any of the other polynucleotide sequences describedherein. For example, without limitation thereto, the present inventioncontemplates antibodies comprising the combination of any of thevariable light chain and variable heavy chain sequences describedherein, and further contemplates antibodies resulting from substitutionof any of the CDR sequences described herein for any of the other CDRsequences described herein. As noted preferred anti-IL-6 antibodies orfragments may contain a variable heavy and/or light sequence as shown inFIG. 15 or FIG. 16, such as SEQ ID NO:651, 657, 709 or variants thereofwherein one or more CDR or FR residues are modified without adverselyaffecting antibody binding to IL-6 or other desired functional activity.

Additional Exemplary Embodiments of the Invention

In another embodiment, the invention contemplates one or more anti-humanIL-6 antibodies or antibody fragment which specifically bind to the samelinear or conformational epitope(s) and/or competes for binding to thesame linear or conformational epitope(s) on an intact human IL-6polypeptide or fragment thereof as an anti-human IL-6 antibody selectedfrom the group consisting of Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8,Ab9, Ab10, Ab11, Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20,Ab21, Ab22, Ab23, Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32,Ab33, Ab34, Ab35, and Ab36 or humanized versions such as thosecontaining the heavy and light chain region humanized versions depictedin FIG. 15. In a preferred embodiment, the anti-human IL-6 antibody orfragment specifically binds to the same linear or conformationalepitope(s) and/or competes for binding to the same linear orconformational epitope(s) on an intact human IL-6 polypeptide or afragment thereof as Ab1.

In another embodiment of the invention, the anti-human IL-6 antibodywhich specifically binds to the same linear or conformational epitopeson an intact IL-6 polypeptide or fragment thereof that is (are)specifically bound by Ab1 binds to a IL-6 epitope(s) ascertained byepitopic mapping using overlapping linear peptide fragments which spanthe full length of the native human IL-6 polypeptide. In one embodimentof the invention, the IL-6 epitope comprises, or alternatively consistsof, one or more residues comprised in IL-6 fragments selected from thoserespectively encompassing amino acid residues 37-51, amino acid residues70-84, amino acid residues 169-183, amino acid residues 31-45 and/oramino acid residues 58-72.

The invention is also directed to an anti-IL-6 antibody that binds withthe same IL-6 epitope and/or competes with an anti-IL-6 antibody forbinding to IL-6 as an antibody or antibody fragment disclosed herein,including but not limited to an anti-IL-6 antibody selected from Ab1,Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14,Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26,Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, and Ab36 andhumanized or chimeric or other variants including those containing thehumanized variable heavy and/or light regions contained in FIG. 15.

In another embodiment, the invention is also directed to an isolatedanti-IL-6 antibody or antibody fragment comprising one or more of theCDRs contained in the V_(H) polypeptide sequences selected from thegroup consisting of: SEQ ID NO:3, 18, 19, 665, 22, 668, 38, 672, 54,676,70, 680, 86, 684, 102, 688, 117, 118, 692 123, 139, 155, 171, 187,203, 219, 235, 251, 267, 283, 299, 315, 331, 347, 363, 379, 395, 411,427, 443, 459, 475, 491, 507, 523, 539, 555 and SEQ ID NO:571 or in oneof SEQ ID NOs: 652-658 and/or one or more of the CDRs contained in theV_(L) polypeptide sequence consisting of: 2, 20, 667, 37, 671, 53, 67569, 679, 85, 683, 101, 687, 119, 693, 122, 138, 154, 170, 186, 202, 218,234, 250, 266, 282, 298, 314, 330, 346, 362, 378, 394, 410, 426, 442,458, 474, 490, 506, 522, 538, 554, 709 and SEQ ID NO:570 or in one ofSEQ ID NO:647-651.

In one embodiment of the invention, the anti-human IL-6 antibodydiscussed in the two prior paragraphs comprises at least 2complementarity determining regions (CDRs) in each the variable lightand the variable heavy regions which are identical to those contained inan anti-human IL-6 antibody selected from the group consisting of Ab1,Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11, Ab12, Ab13, Ab14,Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23, Ab24, Ab25, Ab26,Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35, and Ab36.

In a preferred embodiment, the anti-human IL-6 antibody discussed abovecomprises at least 2 complementarity determining regions (CDRs) in eachthe variable light and the variable heavy regions which are identical tothose contained in Ab1. In another embodiment, all of the CDRs of theanti-human IL-6 antibody discussed above are identical to the CDRscontained in an anti-human IL-6 antibody selected from the groupconsisting of Ab1, Ab2, Ab3, Ab4, Ab5, Ab6, Ab7, Ab8, Ab9, Ab10, Ab11,Ab12, Ab13, Ab14, Ab15, Ab16, Ab17, Ab18, Ab19, Ab20, Ab21, Ab22, Ab23,Ab24, Ab25, Ab26, Ab27, Ab28, Ab29, Ab30, Ab31, Ab32, Ab33, Ab34, Ab35,and Ab36. In a preferred embodiment of the invention, all of the CDRs ofthe anti-human IL-6 antibody discussed above are identical to the CDRscontained in Ab1 or an anti-IL-6 antibody comprising the CDRs containedin the variable heavy and light chain polypeptides contained in SEQ IDNO:651 or 709 and SEQ ID NO:657 as shown in FIGS. 15 and 16.

The invention further contemplates that the one or more anti-human IL-6antibodies discussed above are aglycosylated; that contain an Fc regionthat has been modified to alter effector function, half-life,proteolysis, and/or glycosylation; are human, humanized, single chain orchimeric; and are a humanized antibody derived from a rabbit (parent)anti-human IL-6 antibody.

The invention further contemplates one or more anti-human IL-6antibodies wherein the framework regions (FRs) in the variable lightregion and the variable heavy regions of said antibody respectively arehuman FRs which are unmodified or which have been modified by thesubstitution of at most 2 or 3 human FR residues in the variable lightor heavy chain region with the corresponding FR residues of the parentrabbit antibody, and wherein said human FRs have been derived from humanvariable heavy and light chain antibody sequences which have beenselected from a library of human germline antibody sequences based ontheir high level of homology to the corresponding rabbit variable heavyor light chain regions relative to other human germline antibodysequences contained in the library.

In one embodiment of the invention, the anti-human IL-6 antibody orfragment specifically binds to IL-6 expressing human cells and/or tocirculating soluble IL-6 molecules in vivo, including IL-6 expressed onor by human cells in a patient with a disease associated with cells thatexpress IL-6.

In another embodiment, the disease is selected from general fatigue,exercise-induced fatigue, cancer-related fatigue, inflammatorydisease-related fatigue, chronic fatigue syndrome, cancer-relatedcachexia, cardiac-related cachexia, respiratory-related cachexia,renal-related cachexia, age-related cachexia, rheumatoid arthritis,systemic lupus erythematosis (SLE), systemic juvenile idiopathicarthritis, psoriasis, psoriatic arthropathy, ankylosing spondylitis,inflammatory bowel disease (IBD), polymyalgia rheumatica, giant cellarteritis, autoimmune vasculitis, graft versus host disease (GVHD),Sjogren's syndrome, adult onset Still's disease, rheumatoid arthritis,systemic juvenile idiopathic arthritis, osteoarthritis, osteoporosis,Paget's disease of bone, osteoarthritis, multiple myeloma, Hodgkin'slymphoma, non-Hodgkin's lymphoma, prostate cancer, leukemia, renal cellcancer, multicentric Castleman's disease, ovarian cancer, drugresistance in cancer chemotherapy, cancer chemotherapy toxicity,ischemic heart disease, atherosclerosis, obesity, diabetes, asthma,multiple sclerosis, Alzheimer's disease, cerebrovascular disease, fever,acute phase response, allergies, anemia, anemia of inflammation (anemiaof chronic disease), hypertension, depression, depression associatedwith a chronic illness, thrombosis, thrombocytosis, acute heart failure,metabolic syndrome, miscarriage, obesity, chronic prostatitis,glomerulonephritis, pelvic inflammatory disease, reperfusion injury,transplant rejection, graft versus host disease (GVHD), avian influenza,smallpox, pandemic influenza, adult respiratory distress syndrome(ARDS), severe acute respiratory syndrome (SARS), sepsis, and systemicinflammatory response syndrome (SIRS). In a preferred embodiment, thedisease is selected from a cancer, inflammatory disorder, viraldisorder, or autoimmune disorder. In a particularly preferredembodiment, the disease is arthritis, cachexia, and wasting syndrome

The invention further contemplates anti-human IL-6 antibodies orfragments directly or indirectly attached to a detectable label ortherapeutic agent.

The invention also contemplates one or more nucleic acid sequences whichresult in the expression of an anti-human IL-6 antibody or antibodyfragment as set forth above, including those comprising, oralternatively consisting of, yeast or human preferred codons. Theinvention also contemplates vectors (including plasmids or recombinantviral vectors) comprising said nucleic acid sequence(s). The inventionalso contemplates host cells or recombinant host cells expressing atleast one of the antibodies set forth above, including a mammalian,yeast, bacterial, and insect cells. In a preferred embodiment, the hostcell is a yeast cell. In a further preferred embodiment, the yeast cellis a diploidal yeast cell. In a more preferred embodiment, the yeastcell is a Pichia yeast.

The invention also contemplates a method of treatment comprisingadministering to a patient with a disease or condition associated withIL-6 expressing cells a therapeutically effective amount of at least oneanti-human IL-6 antibody or fragment. The diseases that may be treatedare presented in the non-limiting list set forth above. In a preferredembodiment, the disease is selected from a cancer, autoimmune disease,or inflammatory condition. In a particularly preferred embodiment, thedisease is cancer or viral infection. In another embodiment thetreatment further includes the administration of another therapeuticagent or regimen selected from chemotherapy, radiotherapy, cytokineadministration or gene therapy.

The invention further contemplates a method of in vivo imaging whichdetects the presence of cells which express IL-6 comprisingadministering a diagnostically effective amount of at least oneanti-human IL-6 antibody. In one embodiment, said administration furtherincludes the administration of a radionuclide or fluorophore thatfacilitates detection of the antibody at IL-6 expressing disease sites.In another embodiment of the invention, the method of in vivo imaging isused to detect IL-6 expressing tumors or metastases or is used to detectthe presence of sites of autoimmune disorders associated with IL-6expressing cells. In a further embodiment, the results of said in vivoimaging method are used to facilitate design of an appropriatetherapeutic regimen, including therapeutic regimens includingradiotherapy, chemotherapy or a combination thereof.

Polynucleotides Encoding Anti-IL-6 Antibody Polypeptides

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:2 as shown below or SEQ ID NO:660 or the humanized versionsthereof contained in SEQ ID NO:647, 648, 649, 650, 651, or 709:

(SEq ID NO: 10) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGCCTATGATATGACCCAGACTCCAGCCTCGGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGCATTAACAATGAATTATCCTGGTATCAGCAGAAACCAGGGCAGCGTCCCAAGCTCCTGATCTATAGGGCATCCACTCTGGCATCTGGGGTCTCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAACAGGGTTATAGTCTGAGGAATATTGATAATGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAAACGTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTor the polynucleotide sequence of SEQ ID NO:662, 698, 701, or 705.

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:3 below or in SEQ ID NO:661 or the humanized versions thereofcontained in SEQ ID NO:652, 653, 654, 655, 656, 657 or 658:

(SEQ ID NO: 11) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGCCTCTGGATTCTCCCTCAGTAACTACTACGTGACCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGAATCATTTATGGTAGTGATGAAACGGCCTACGCGACCTGGGCGATAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGAAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTCTGTGCCAGAGATGATAGTAGTGACTGGGATGCAAAATTTAACTTGTGGGGCCAAGGCACCCTGGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGor the polynucleotide sequence of SEQ ID NO:663, 700, 703, or 707.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:12 or 694; SEQ ID NO:13; and SEQ ID NO:14 or 695 whichcorrespond to polynucleotides encoding the complementarity-determiningregions (CDRs, or hypervariable regions) of the light chain variablesequence of SEQ ID NO:2.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:15; SEQ ID NO:16 or 696; and SEQ ID NO:17 or 697 whichcorrespond to polynucleotides encoding the complementarity-determiningregions (CDRs, or hypervariable regions) of the heavy chain variablesequence of SEQ ID NO:3 or SEQ ID NO:661 or SEQ ID NO:657 or othersdepicted in FIG. 15.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:10, 662, 698, 701, or 705encoding the light chain variable region of SEQ ID NO:2, 20, 647, 648,649, 650, 651, 660, 666, 699, 702, 706, or 709 or a polynucleotideencoding SEQ ID NO:2, 20, 647, 648, 649, 650, 651, 660, 666, 699, 702,706, or 709 or others depicted in FIG. 15; the polynucleotide in SEQ IDNO:10, 662, 698, 701, or 705 encoding the light chain of Ab1, thepolynucleotide SEQ ID NO:11 encoding the heavy chain variable region ofSEQ ID NO:3 or a polynucleotide encoding the variable chain heavy regionin SEQ ID NO:3, 18, 19, 652, 653, 654, 655, 656, 657, 661, 664, 665,657, 658, 704, or 708 or others depicted in FIG. 15; polynucleotidesencoding one or more of the complementarity-determining regions (SEQ IDNO:12 or 694; SEQ ID NO:13; and SEQ ID NO:14 or 695) of the light chainvariable region of SEQ ID NO:10, 662, 698, 701, or 705; andpolynucleotides encoding the complementarity-determining regions (SEQ IDNO:15; SEQ ID NO:16 or 696; and SEQ ID NO:17 or 697) of the heavy chainvariable region of SEQ ID NO:11, 663, 700, 703, or 707 or those encodingthe CDRs in the variable chain heavy region contained in SEQ ID NO:3,18, 19, 652, 653, 654, 655, 656, 657, 661, 664, 665, 657, 658, 704, or708.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:21 below (or the polynucleotide of SEQ ID NO:669 encoding SEQ IDNO:667):

(SEQ ID NO: 29) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGCCTATGATATGACCCAGACTCCAGCCTCTGTGGAGGTAGCTGTGGGAGGCACAGTCACCATCAATTGCCAGGCCAGTGAGACCATTTACAGTTGGTTATCCTGGTATCAGCAGAAGCCAGGGCAGCCTCCCAAGCTCCTGATCTACCAGGCATCCGATCTGGCATCTGGGGTCCCATCGCGATTCAGCGGCAGTGGGGCTGGGACAGAGTACACTCTCACCATCAGCGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGTCAACAGGGTTATAGTGGTAGTAATGTTGATAATGTTTTCGGCGGAGGGACCGAGGTGGTGGTCAAACGTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATC CCAGAGAGGCCAAAG

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:22 as below (or the polynucleotide of SEQ ID NO:670 encoding SEQID NO:668):

(SEQ ID NO: 30) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGGAGCAGCTGAAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTTACCTGCACAGCCTCTGGATTCTCCCTCAATGACCATGCAATGGGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATACATCGGATTCATTAATAGTGGTGGTAGCGCACGCTACGCGAGCTGGGCAGAAGGCCGATTCACCATCTCCAGAACCTCGACCACGGTGGATCTGAAAATGACCAGTCTGACAACCGAGGACACGGCCACCTATTTCTGTGTCAGAGGGGGTGCTGTTTGGAGTATTCATAGTTTTGATCCCTGGGGCCCAGGGACCCTGGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGG TCAAG.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:31; SEQ ID NO:32; and SEQ ID NO:33 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:21 or SEQ ID NO:667.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:34; SEQ ID NO:35; and SEQ ID NO:36 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:22 or SEQ ID NO:668.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:29 or SEQ ID NO:669 encoding thelight chain variable region of SEQ ID NO:21 or SEQ ID NO:667; thepolynucleotide SEQ ID NO:30 or SEQ ID NO:670 encoding the heavy chainvariable region of SEQ ID NO:22 or SEQ ID NO:668; polynucleotidesencoding the complementarity-determining regions (SEQ ID NO:31; SEQ IDNO:32; and SEQ ID NO:33) of the light chain variable region of SEQ IDNO:29; and polynucleotides encoding the complementarity-determiningregions (SEQ ID NO:34; SEQ ID NO:35; and SEQ ID NO:36) of the heavychain variable region of SEQ ID NO:30.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:37 as set forth below (or the polynucleotide of SEQ ID NO:673encoding SEQ ID NO:671):

(SEQ ID NO: 45) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCCGCCGTGCTGACCCAGACTCCATCTCCCGTGTCTGCAGCTGTGGGAGGCACAGTCAGCATCAGTTGCCAGGCCAGTCAGAGTGTTTATGACAACAACTACTTATCCTGGTTTCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGGTGCATCCACTCTGGCATCTGGGGTCCCATCGCGGTTCGTGGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCACAGACGTGCAGTGTGACGATGCTGCCACTTACTATTGTGCAGGCGTTTATGATGATGATAGTGATAATGCCTTCGGCGGAGGGACCGAGGTGGTGGTCAAACGTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:38 (or the polynucleotide of SEQ ID NO:674 encoding SEQ IDNO:672):

(SEQ ID NO: 46) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTGGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACCCCTGGGACACCCCTGACACTCACCTGCACAGCCTCTGGATTCTCCCTCAGTGTCTACTACATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGATTCATTACAATGAGTGATAATATAAATTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGAAAATGACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGGAGTCGTGGCTGGGGTACAATGGGTCGGTTGGATCTCTGGGGCCCAGGCACCCTCGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCA AGG.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:47; SEQ ID NO:48; and SEQ ID NO:49 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:37 or SEQ ID NO:671.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:50; SEQ ID NO:51; and SEQ ID NO:52 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:38 or SEQ ID NO:672.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:45 or SEQ ID NO:673 encoding thelight chain variable region of SEQ ID NO:37 or SEQ ID NO:671; thepolynucleotide SEQ ID NO:46 or SEQ ID NO:674 encoding the heavy chainvariable region of SEQ ID NO:38; polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:47; SEQ ID NO:48; and SEQID NO:49) of the light chain variable region of SEQ ID NO:37 or SEQ IDNO:671; and polynucleotides encoding the complementarity-determiningregions (SEQ ID NO:50; SEQ ID NO:51; and SEQ ID NO:52) of the heavychain variable region of SEQ ID NO:38 or SEQ ID NO:672.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:53 as shown below (or the polynucleotide of SEQ ID NO: 677encoding SEQ ID NO:675):

(SEQ ID NO: 61) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCATATGTGACCCTGTGCTGACCCAGACTCCATCTCCCGTATCTGCACCTGTGGGAGGCACAGTCAGCATCAGTTGCCAGGCCAGTCAGAGTGTTTATGAGAACAACTATTTATCCTGGTTTCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGGTGCATCCACTCTGGATTCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATTACAGACGTGCAGTGTGACGATGCTGCCACTTACTATTGTGCAGGCGTTTATGATGATGATAGTGATGATGCCTTCGGCGGAGGGACCGAGGTGGTGGTCAAACGTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:54 (or the polynucleotide of SEQ ID NO:678 encoding SEQ IDNO:676):

(SEQ ID NO: 62) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTGGCTGTGCTCAAAGGTGTCCAGTGTCAGGAGCAGCTGAAGGAGTCCGGAGGAGGCCTGGTAACGCCTGGAGGAACCCTGACACTCACCTGCACAGCCTCTGGATTCTCCCTCAATGCCTACTACATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGATTCATTACTCTGAATAATAATGTAGCTTACGCGAACTGGGCGAAAGGCCGATTCACCTTCTCCAAAACCTCGACCACGGTGGATCTGAAAATGACCAGTCCGACACCCGAGGACACGGCCACCTATTTCTGTGCCAGGAGTCGTGGCTGGGGTGCAATGGGTCGGTTGGATCTCTGGGGCCATGGCACCCTGGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGG TCAAGG.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:63; SEQ ID NO:64; and SEQ ID NO:65 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:53 or SEQ ID NO:675.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:66; SEQ ID NO:67; and SEQ ID NO:68 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:54 or SEQ ID NO:676.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:61 or SEQ ID NO:677 encoding thelight chain variable region of SEQ ID NO:53 or SEQ ID NO:675; thepolynucleotide SEQ ID NO:62 or SEQ ID NO:678 encoding the heavy chainvariable region of SEQ ID NO:54 or SEQ ID NO:676; polynucleotidesencoding the complementarity-determining regions (SEQ ID NO:63; SEQ IDNO:64; and SEQ ID NO:65) of the light chain variable region of SEQ IDNO:53 or SEQ ID NO:675; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:66; SEQ ID NO:67; and SEQID NO:68) of the heavy chain variable region of SEQ ID NO:54 or SEQ IDNO:676.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:69 (or the polynucleotide of SEQ ID NO:681 encoding SEQ IDNO:679):

(SEQ ID NO: 77) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCCCAAGTGCTGACCCAGACTCCATCGCCTGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAACTGCCAGGCCAGTCAGAGTGTTGATGATAACAACTGGTTAGGCTGGTATCAGCAGAAACGAGGGCAGCCTCCCAAGTACCTGATCTATTCTGCATCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGACCTGGAGTGTGACGATGCTGCCACTTACTACTGTGCAGGCGGTTTTAGTGGTAATATCTTTGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAAACGTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:70 (or the polynucleotide of SEQ ID NO:682 encoding SEQ IDNO:680):

(SEQ ID NO: 78) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGTCTCTGGCTTCTCCCTCAGTAGCTATGCAATGAGCTGGGTCCGCCAGGCTCCAGGAAAGGGGCTGGAGTGGATCGGAATCATTGGTGGTTTTGGTACCACATACTACGCGACCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGAGAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGGTGGTCCTGGTAATGGTGGTGACATCTGGGGCCAAGGGACCCTGGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACT.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:79; SEQ ID NO:80; and SEQ ID NO:81 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:69.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:82; SEQ ID NO:83; and SEQ ID NO:84 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:70.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:77 or SEQ ID NO:681 encoding thelight chain variable region of SEQ ID NO:69 or in SEQ ID NO:679; thepolynucleotide SEQ ID NO:78 or SEQ ID NO:682 encoding the heavy chainvariable region of SEQ ID NO:70 or SEQ ID NO:680; polynucleotidesencoding the complementarity-determining regions (SEQ ID NO:79; SEQ IDNO:80; and SEQ ID NO:81) of the light chain variable region of SEQ IDNO:69; and polynucleotides encoding the complementarity-determiningregions (SEQ ID NO:82; SEQ ID NO:83; and SEQ ID NO:84) of the heavychain variable region of SEQ ID NO:70.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:85 (or the polynucleotide of SEQ ID NO: 685 encoding SEQ IDNO:683):

(SEQ ID NO: 93) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCAGCCGTGCTGACCCAGACACCATCGCCCGTGTCTGTACCTGTGGGAGGCACAGTCACCATCAAGTGCCAGTCCAGTCAGAGTGTTTATAATAATTTCTTATCGTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACCAGGCATCCAAACTGGCATCTGGGGTCCCAGATAGGTTCAGCGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGTCTAGGCGGTTATGATGATGATGCTGATAATGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAAACGTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTC

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:86 (or the polynucleotide of SEQ ID NO: 686 encoding SEQ IDNO:684):

(SEQ ID NO: 94) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACGCTCACCTGCACAGTCTCTGGAATCGACCTCAGTGACTATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGAATCATTTATGCTGGTAGTGGTAGCACATGGTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGATGGATACGATGACTATGGTGATTTCGATCGATTGGATCTCTGGGGCCCAGGCACCCTCGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCT GCCTGGTCAAGGACT.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:95; SEQ ID NO:96; and SEQ ID NO:97 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:85 or SEQ ID NO:683.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:98; SEQ ID NO:99; and SEQ ID NO:100 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:86.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:93 or SEQ ID NO:685 encoding thelight chain variable region of SEQ ID NO:85 or SEQ ID NO:683; thepolynucleotide SEQ ID NO:94 or SEQ ID NO:686 encoding the heavy chainvariable region of SEQ ID NO:86 or SEQ ID NO:684; polynucleotidesencoding the complementarity-determining regions (SEQ ID NO:95; SEQ IDNO:96; and SEQ ID NO:97) of the light chain variable region of SEQ IDNO:85 or SEQ ID NO:683; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:98; SEQ ID NO:99; and SEQID NO:100) of the heavy chain variable region of SEQ ID NO:86.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:101 (or the polynucleotide of SEQ ID NO: 689 encoding SEQ IDNO:687):

(SEQ ID NO: 109) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGCCTATGATATGACCCAGACTCCAGCCTCGGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAAATGCCAGGCCAGTCAGAGCATTAACAATGAATTATCCTGGTATCAGCAGAAATCAGGGCAGCGTCCCAAGCTCCTGATCTATAGGGCATCCACTCTGGCATCTGGGGTCTCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAACAGGGTTATAGTCTGAGGAATATTGATAATGCTTTCGGCGGAGGGACCGAGGTGGTGGTCAAACGTACGGTAGCGGCCCCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTC

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:102 (or the polynucleotide of SEQ ID NO: 690 encoding SEQ IDNO:688):

(SEQ ID NO: 110) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCTCAGGTGTCCAGTGTCAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGCCTCTGGATTCTCCCTCAGTAACTACTACATGACCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGAATGATTTATGGTAGTGATGAAACAGCCTACGCGAACTGGGCGATAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGAAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTCTGTGCCAGAGATGATAGTAGTGACTGGGATGCAAAATTTAACTTGTGGGGCCAAGGGACCCTCGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAA GG.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:111; SEQ ID NO:112; and SEQ ID NO:113 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:101 or 687.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:114; SEQ ID NO:115; and SEQ ID NO:116 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:102 or 688.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:109 or SEQ ID NO:689 encodingthe light chain variable region of SEQ ID NO:101 or 687; thepolynucleotide or SEQ ID NO:690 encoding the heavy chain variable regionof SEQ ID NO:102 or 688; polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:111; SEQ ID NO:112; andSEQ ID NO:113) of the light chain variable region of SEQ ID NO:101 or687; and polynucleotides encoding the complementarity-determiningregions (SEQ ID NO:114; SEQ ID NO:115; and SEQ ID NO:116) of the heavychain variable region of SEQ ID NO:102 or 688.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:122:

(SEQ ID NO: 130) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCAGCCGTGCTGACCCAGACACCATCACCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAGTTGCCAGTCCAGTCAGAGTGTTGGTAATAACCAGGACTTATCCTGGTTTCAGCAGAGACCAGGGCAGCCTCCCAAGCTCCTGATCTACGAAATATCCAAACTGGAATCTGGGGTCCCATCGCGGTTCAGCGGCAGTGGATCTGGGACACACTTCACTCTCACCATCAGCGGCGTACAGTGTGACGATGCTGCCACTTACTACTGTCTAGGCGGTTATGATGATGATGCTGATAATGCT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:123:

(SEQ ID NO: 131) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCACTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGTCTCTGGATTCTCCCTCAGTAGTCGTACAATGTCCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGATACATTTGGAGTGGTGGTAGCACATACTACGCGACCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGATTGGGCGATACTGGTGGTCACGCTTATGCTACTCGCTTAAATCTC.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:132; SEQ ID NO:133; and SEQ ID NO:134 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:122.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:135; SEQ ID NO:136; and SEQ ID NO:137 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:123.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:130 encoding the light chainvariable region of SEQ ID NO:122; the polynucleotide SEQ ID NO:131encoding the heavy chain variable region of SEQ ID NO:123;polynucleotides encoding the complementarity-determining regions (SEQ IDNO:132; SEQ ID NO:133; and SEQ ID NO:134) of the light chain variableregion of SEQ ID NO:122; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:135; SEQ ID NO:136; andSEQ ID NO:137) of the heavy chain variable region of SEQ ID NO:123.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:138:

(SEQ ID NO: 146) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCAGCCGTGCTGACCCAGACACCATCGTCCGTGTCTGCAGCTGTGGGAGGCACAGTCAGCATCAGTTGCCAGTCCAGTCAGAGTGTTTATAGTAATAAGTACCTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACTGGACATCCAAACTGGCATCTGGGGCCCCATCACGGTTCAGCGGCAGTGGATCTGGGACACAATTCACTCTCACCATCAGCGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGTCTAGGCGCTTATGATGATGATGCTGATAATGCT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:139:

(SEQ ID NO: 147) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGGTGGAAGAGTCCGGGGGTCGCCTGGTCAAGCCTGACGAAACCCTGACACTCACCTGCACAGCCTCTGGATTCTCCCTGGAGGGCGGCTACATGACCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGAATCAGTTATGATAGTGGTAGCACATACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAGACCTCGTCGACCACGGTGGATCTGAAAATGACCAGTCTGACAACCGAGGACACGGCCACCTATTTCTGCGTCAGATCACTAAAATATCCTACTGTTACTTCTGATGACTTG.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:148; SEQ ID NO:149; and SEQ ID NO:150 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:138.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:151; SEQ ID NO:152; and SEQ ID NO:153 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:139.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:146 encoding the light chainvariable region of SEQ ID NO:138; the polynucleotide SEQ ID NO:147encoding the heavy chain variable region of SEQ ID NO:139;polynucleotides encoding the complementarity-determining regions (SEQ IDNO:148; SEQ ID NO:149; and SEQ ID NO:150) of the light chain variableregion of SEQ ID NO:138; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:151; SEQ ID NO:152; andSEQ ID NO:153) of the heavy chain variable region of SEQ ID NO:139.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:154:

(SEQ ID NO: 162) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCAGCCGTGCTGACCCAGACACCATCACCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAGTTGCCAGTCCAGTCAGAGTGTTTATAATAATAACGACTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCTAAACTCCTGATCTATTATGCATCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGGCGTGCAGTGTGACGATGCTGCCGCTTACTACTGTCTAGGCGGTTATGATGATGATGCTGATAATGCT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:155:

(SEQ ID NO: 163) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGTATCTGGATTATCCCTCAGTAGCAATACAATAAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGGATACATTTGGAGTGGTGGTAGTACATACTACGCGAGCTGGGTGAATGGTCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGGGGGTTACGCTAGTGGTGGTTATCCTTATGCCACTCGGTTGGATCTC.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:164; SEQ ID NO:165; and SEQ ID NO:166 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:154.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:167; SEQ ID NO:168; and SEQ ID NO:169 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:155.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:162 encoding the light chainvariable region of SEQ ID NO:154; the polynucleotide SEQ ID NO:163encoding the heavy chain variable region of SEQ ID NO:155;polynucleotides encoding the complementarity-determining regions (SEQ IDNO:164; SEQ ID NO:165; and SEQ ID NO:166) of the light chain variableregion of SEQ ID NO:154; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:167; SEQ ID NO:168; andSEQ ID NO:169) of the heavy chain variable region of SEQ ID NO:155.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:170:

(SEQ ID NO: 178) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCAGCCGTGCTGACCCAGACACCATCCTCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAATTGCCAGTCCAGTCAGAGTGTTTATAATAACGACTACTTATCCTGGTATCAACAGAGGCCAGGGCAACGTCCCAAGCTCCTAATCTATGGTGCTTCCAAACTGGCATCTGGGGTCCCGTCACGGTTCAAAGGCAGTGGATCTGGGAAACAGTTTACTCTCACCATCAGCGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGTCTGGGCGATTATGATGATGATGCTGATAATACT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:171:

(SEQ ID NO: 179) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACTTGCACAGTCTCTGGATTCACCCTCAGTACCAACTACTACCTGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTAGAATGGATCGGAATCATTTATCCTAGTGGTAACACATATTGCGCGAAGTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGGATCTGAAAATGACCAGTCCGACAACCGAGGACACAGCCACGTATTTCTGTGCCAGAAATTATGGTGGTGATGAAAGTTTG.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:180; SEQ ID NO:181; and SEQ ID NO:182 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:170.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:183; SEQ ID NO:184; and SEQ ID NO:185 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:171.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:178 encoding the light chainvariable region of SEQ ID NO:170; the polynucleotide SEQ ID NO:179encoding the heavy chain variable region of SEQ ID NO:171;polynucleotides encoding the complementarity-determining regions (SEQ IDNO:180; SEQ ID NO:181; and SEQ ID NO:182) of the light chain variableregion of SEQ ID NO:170; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:183; SEQ ID NO:184; andSEQ ID NO:185) of the heavy chain variable region of SEQ ID NO:171.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:186:

(SEQ ID NO: 194) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGATGTTGTGATGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTGAGACCATTGGCAATGCATTAGCCTGGTATCAGCAGAAATCAGGGCAGCCTCCCAAGCTCCTGATCTACAAGGCATCCAAACTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTACACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAATGGTGTTATTTTG GTGATAGTGTT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:187:

(SEQ ID NO: 195) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCACTGTGCTCAAAGGTGTCCAGTGTCAGGAGCAGCTGGTGGAGTCCGGGGGAGGCCTGGTCCAGCCTGAGGGATCCCTGACACTCACCTGCACAGCCTCTGGATTCGACTTCAGTAGCGGCTACTACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCGTGTATTTTCACTATTACTACTAACACTTACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAGACCTCGTCGACCACGGTGACTCTGCAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATCTCTGTGCGAGAGGGATTTATTCTGATAATAATTATTATGCCTTG.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:196; SEQ ID NO:197; and SEQ ID NO:198 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:186.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:199; SEQ ID NO:200; and SEQ ID NO:201 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:187.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:194 encoding the light chainvariable region of SEQ ID NO:186; the polynucleotide SEQ ID NO:195encoding the heavy chain variable region of SEQ ID NO:187;polynucleotides encoding the complementarity-determining regions (SEQ IDNO:196; SEQ ID NO:197; and SEQ ID NO:198) of the light chain variableregion of SEQ ID NO:186; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:199; SEQ ID NO:200; andSEQ ID NO:201) of the heavy chain variable region of SEQ ID NO:187.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:202:

(SEQ ID NO: 210) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGATGTTGTGATGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTGAGAGCATTGGCAATGCATTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACAAGGCATCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGGCGTGCAGTGTGCCGATGCTGCCGCTTACTACTGTCAATGGTGTTATTTTG GTGATAGTGTT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:203:

(SEQ ID NO: 211) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGCAGCAGCTGGTGGAGTCCGGGGGAGGCCTGGTCAAGCCGGGGGCATCCCTGACACTCACCTGCAAAGCCTCTGGATTCTCCTTCAGTAGCGGCTACTACATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTCGATCGCATGCATTTTTACTATTACTGATAACACTTACTACGCGAACTGGGCGAAAGGCCGATTCACCATCTCCAAGCCCTCGTCGCCCACGGTGACTCTGCAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTCTGTGCGAGGGGGATTTATTCTACTGATAATTATTATGCCTTG.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:212; SEQ ID NO:213; and SEQ ID NO:214 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:202.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:215; SEQ ID NO:216; and SEQ ID NO:217 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:203.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:210 encoding the light chainvariable region of SEQ ID NO:202; the polynucleotide SEQ ID NO:211encoding the heavy chain variable region of SEQ ID NO:203;polynucleotides encoding the complementarity-determining regions (SEQ IDNO:212; SEQ ID NO:213; and SEQ ID NO:214) of the light chain variableregion of SEQ ID NO:202; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:215; SEQ ID NO:216; andSEQ ID NO:217) of the heavy chain variable region of SEQ ID NO:203.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:218:

(SEQ ID NO: 226) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGATGTTGTGATGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGCGTTAGTAGCTACTTAAACTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACAGGGCATCCACTCTGGAATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAATGTACTTATGGTACTAGTAGTAGTTATGGTGCTGCT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:219:

(SEQ ID NO: 227) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACCGTCTCTGGTATCTCCCTCAGTAGCAATGCAATAAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGAATCATTAGTTATAGTGGTACCACATACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGGATCTGAAAATCACTAGTCCGACAACCGAGGACACGGCCACCTACTTCTGTGCCAGAGATGACCCTACGACAGTTATGGTTATGTTGATACCTTTTGGAGCCGGCATGGAC CTC.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:228; SEQ ID NO:229; and SEQ ID NO:230 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:218.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:231; SEQ ID NO:232; and SEQ ID NO:233 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:219.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:226 encoding the light chainvariable region of SEQ ID NO:218; the polynucleotide SEQ ID NO:227encoding the heavy chain variable region of SEQ ID NO:219;polynucleotides encoding the complementarity-determining regions (SEQ IDNO:228; SEQ ID NO:229; and SEQ ID NO:230) of the light chain variableregion of SEQ ID NO:218; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:231; SEQ ID NO:232; andSEQ ID NO:233) of the heavy chain variable region of SEQ ID NO:219.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:234:

(SEQ ID NO: 242) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCCCAAGTGCTGACCCAGACTGCATCGCCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAACTGCCAGGCCAGTCAGAGTGTTTATAAGAACAACTACTTATCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAAGGCCTGATCTATTCTGCATCGACTCTAGATTCTGGGGTCCCATTGCGGTTCAGCGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGACGTGCAGTGTGACGATGCTGCCACTTACTACTGTCTAGGCAGTTATGATTGTAGTAGTGGTGATTGTTATGCT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:235:

(SEQ ID NO: 243) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGTTGGAGGAGTCCGGGGGAGACCTGGTCAAGCCTGAGGGATCCCTGACACTCACCTGCACAGCCTCTGGATTCTCCTTCAGTAGCTACTGGATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTGTTACTGGTAATGGTAACACTTACTACGCGAACTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGACTCTGCAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTTTGTGCGAAAG CCTATGACTTG.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:244; SEQ ID NO:245; and SEQ ID NO:246 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:234.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:247; SEQ ID NO:248; and SEQ ID NO:249 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:235.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:242 encoding the light chainvariable region of SEQ ID NO:234; the polynucleotide SEQ ID NO:243encoding the heavy chain variable region of SEQ ID NO:235;polynucleotides encoding the complementarity-determining regions (SEQ IDNO:244; SEQ ID NO:245; and SEQ ID NO:246) of the light chain variableregion of SEQ ID NO:234; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:247; SEQ ID NO:248; andSEQ ID NO:249) of the heavy chain variable region of SEQ ID NO:235.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:250:

(SEQ ID NO: 258) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTTCCACATTTGCCGCCGTGCTGACCCAGACTCCATCTCCCGTGTCTGCAGCTGTGGGAGGCACAGTCAGCATCAGTTGCCAGGCCAGTCAGAGTGTTTATGACAACAACTATTTATCCTGGTATCAGCAGAAACCAGGACAGCCTCCCAAGCTCCTGATCTATGGTGCATCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCACGGGATCTGGGACACAGTTCACTCTCACCATCACAGACGTGCAGTGTGACGATGCTGCCACTTACTATTGTGCAGGCGTTTTTAATGATGATAGTGATGATGCC

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:251:

(SEQ ID NO: 259) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCCCAAAGGTGTCCAGTGTCAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACACTCTCTGGATTCTCCCTCAGTGCATACTATATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGATTCATTACTCTGAGTGATCATATATCTTACGCGAGGTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGAAAATGACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGGAGTCGTGGCTGGGGTGCAATGGGTCGGTTGGATCTC.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:260; SEQ ID NO:261; and SEQ ID NO:262 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:250.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:263; SEQ ID NO:264; and SEQ ID NO:265 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:251.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:258 encoding the light chainvariable region of SEQ ID NO:250; the polynucleotide SEQ ID NO:259encoding the heavy chain variable region of SEQ ID NO:251;polynucleotides encoding the complementarity-determining regions (SEQ IDNO:260; SEQ ID NO:261; and SEQ ID NO:262) of the light chain variableregion of SEQ ID NO:250; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:263; SEQ ID NO:264; andSEQ ID NO:265) of the heavy chain variable region of SEQ ID NO:251.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:266:

(SEQ ID NO: 274) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTCGCAGCCGTGCTGACCCAGACACCATCGCCCGTGTCTGCGGCTGTGGGAGGCACAGTCACCATCAGTTGCCAGGCCAGTCAGAGTGTTTATAACAACAAAAATTTAGCCTGGTATCAGCAGAAATCAGGGCAGCCTCCCAAGCTCCTGATCTACTGGGCATCCACTCTGGCATCTGGGGTCTCATCGCGGTTCAGCGGCAGTGGATCTGGGACACAGTTCACTCTCACCGTCAGCGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGTCTAGGCGTTTTTGATGATGATGCTGATAATGCT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:267:

(SEQ ID NO: 275) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAATGTCAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGCCTCTGGATTCTCCCTCAGTAGCTACTCCATGACCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATATATCGGAGTCATTGGTACTAGTGGTAGCACATACTACGCGACCTGGGCGAAAGGCCGATTCACCATCTCCAGAACCTCGACCACGGTGGCTCTGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGTCAGGAGTCTTT CTTCTATTACTTTCTTG.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:276; SEQ ID NO:277; and SEQ ID NO:278 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:266.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:279; SEQ ID NO:280; and SEQ ID NO:281 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:267.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:274 encoding the light chainvariable region of SEQ ID NO:266; the polynucleotide SEQ ID NO:275encoding the heavy chain variable region of SEQ ID NO:267;polynucleotides encoding the complementarity-determining regions (SEQ IDNO:276; SEQ ID NO:277; and SEQ ID NO:278) of the light chain variableregion of SEQ ID NO:266; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:279; SEQ ID NO:280; andSEQ ID NO:281) of the heavy chain variable region of SEQ ID NO:267.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:282:

(SEQ ID NO: 290) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGCATTCGAATTGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACCATCAATTGCCAGGCCAGTCAGAACATTTATAGATACTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGTTCCTGATCTATCTGGCATCTACTCTGGCATCTGGGGTCCCATCGCGGTTTAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAAAGTTATTATAGTA GTAATAGTGTCGCT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:283:

(SEQ ID NO: 291) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGGAGCAGCTGGTGGAGTCCGGGGGAGACCTGGTCCAGCCTGAGGGATCCCTGACACTCACCTGCACAGCTTCTGAGTTAGACTTCAGTAGCGGCTACTGGATATGCTGGGTCCGCCAGGTTCCAGGGAAGGGGCTGGAGTGGATCGGATGCATTTATACTGGTAGTAGTGGTAGCACTTTTTACGCGAGTTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGACTCTGCAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTCTGTGCGAGAGGTTATAGTGGCTTTGGTTACTTTAAGTTG.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:292; SEQ ID NO:293; and SEQ ID NO:294 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:282.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:295; SEQ ID NO:296; and SEQ ID NO:297 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:283.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:290 encoding the light chainvariable region of SEQ ID NO:282; the polynucleotide SEQ ID NO:291encoding the heavy chain variable region of SEQ ID NO:283;polynucleotides encoding the complementarity-determining regions (SEQ IDNO:292; SEQ ID NO:293; and SEQ ID NO:294) of the light chain variableregion of SEQ ID NO:282; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:295; SEQ ID NO:296; andSEQ ID NO:297) of the heavy chain variable region of SEQ ID NO:283.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:298:

(SEQ ID NO: 306) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGCCTATGATATGACCCAGACTCCAGCCTCTGTGGAGGTAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTGAGGACATTTATAGGTTATTGGCCTGGTATCAACAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGATTCATCCGATCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCGCCATCAGCGGTGTGCAGTGTGACGATGCTGCCACTTACTACTGTCAACAGGCTTGGAGTT ATAGTGATATTGATAATGCT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:299:

(SEQ ID NO: 307) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCGGGGACACCCCTGACACTCACCTGCACAGCCTCTGGATTCTCCCTCAGTAGCTACTACATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGAATCATTACTACTAGTGGTAATACATTTTACGCGAGCTGGGCGAAAGGCCGGCTCACCATCTCCAGAACCTCGACCACGGTGGATCTGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAACTTCTGATATTTTTTATTATCGTAACTTG.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:308; SEQ ID NO:309; and SEQ ID NO:310 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:298.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:311; SEQ ID NO:312; and SEQ ID NO:313 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:299.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:306 encoding the light chainvariable region of SEQ ID NO:298; the polynucleotide SEQ ID NO:307encoding the heavy chain variable region of SEQ ID NO:299;polynucleotides encoding the complementarity-determining regions (SEQ IDNO:308; SEQ ID NO:309; and SEQ ID NO:310) of the light chain variableregion of SEQ ID NO:298; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:311; SEQ ID NO:312; andSEQ ID NO:313) of the heavy chain variable region of SEQ ID NO:299.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:314:

(SEQ ID NO: 322) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACGTTTGCAGCCGTGCTGACCCAGACTGCATCACCCGTGTCTGCCGCTGTGGGAGCCACAGTCACCATCAACTGCCAGTCCAGTCAGAGTGTTTATAATGACATGGACTTAGCCTGGTTTCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATTCTGCATCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAGCGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGTCTAGGCGCTTTTGATGATGATGCTGATAATACT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:315:

(SEQ ID NO: 323) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGTCTCTGGATTCTCCCTCACTAGGCATGCAATAACCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGATGCATTTGGAGTGGTGGTAGCACATACTACGCGACCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTCAGAATCACCAGTCCGACAACCGAGGACACGGCCACCTACTTCTGTGCCAGAGTCATTGGCGATACTGCTGGTTATGCTTATTTTACGGGGCTTGACTTG.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:324; SEQ ID NO:325; and SEQ ID NO:326 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:314.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:327; SEQ ID NO:328; and SEQ ID NO:329 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:315.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:322 encoding the light chainvariable region of SEQ ID NO:314; the polynucleotide SEQ ID NO:323encoding the heavy chain variable region of SEQ ID NO:315;polynucleotides encoding the complementarity-determining regions (SEQ IDNO:324; SEQ ID NO:325; and SEQ ID NO:326) of the light chain variableregion of SEQ ID NO:314; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:327; SEQ ID NO:328; andSEQ ID NO:329) of the heavy chain variable region of SEQ ID NO:315.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:330:

(SEQ ID NO: 338) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGCCTATGATATGACCCAGACTCCAGCCTCTGTGGAGGTAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGTGTTTATAATTGGTTATCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATACTGCATCCAGTCTGGCATCTGGGGTCCCATCGCGGTTCAGTGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGGCGTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAACAGGGTTATACTA GTGATGTTGATAATGTT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:331:

(SEQ ID NO: 339) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGCTGGAGGAGGCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGTCTCTGGAATCGACCTCAGTAGCTATGCAATGGGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATACATCGGAATCATTAGTAGTAGTGGTAGCACATACTACGCGACCTGGGCGAAAGGCCGATTCACCATCTCACAAGCCTCGTCGACCACGGTGGATCTGAAAATTACCAGTCCGACAACCGAGGACTCGGCCACATATTTCTGTGCCAGAGGGGGTGCTGGTAGTGGTGGTGTTTGGCTGCTTGATGGTTTTGATCCC.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:340; SEQ ID NO:341; and SEQ ID NO:342 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:330.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:343; SEQ ID NO:344; and SEQ ID NO:345 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:331.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:338 encoding the light chainvariable region of SEQ ID NO:330; the polynucleotide SEQ ID NO:339encoding the heavy chain variable region of SEQ ID NO:331;polynucleotides encoding the complementarity-determining regions (SEQ IDNO:340; SEQ ID NO:341; and SEQ ID NO:342) of the light chain variableregion of SEQ ID NO:330; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:343; SEQ ID NO:344; andSEQ ID NO:345) of the heavy chain variable region of SEQ ID NO:331.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:346:

(SEQ ID NO: 354) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAAATGTGCCGATGTTGTGATGACCCAGACTCCAGCCTCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAATTGCCAGGCCAGTGAGAACATTTATAATTGGTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATACTGTAGGCGATCTGGCATCTGGGGTCTCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTATTGTCAACAGGGTTATAGTAGTAGTTATGTTGATAATGTT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:347:

(SEQ ID NO: 355) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGGAGCAGCTGAAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGTCTCTGGATTCTCCCTCAATGACTATGCAGTGGGCTGGTTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGATACATTCGTAGTAGTGGTACCACAGCCTACGCGACCTGGGCGAAAGGCCGATTCACCATCTCCGCTACCTCGACCACGGTGGATCTGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGGGGGTGCTGGTAGTAGTGGTGTGTGGATCCTTGATGGTTTTGCTCCC.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:356; SEQ ID NO:357; and SEQ ID NO:358 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:346.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:359; SEQ ID NO:360; and SEQ ID NO:361 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:347.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:354 encoding the light chainvariable region of SEQ ID NO:346; the polynucleotide SEQ ID NO:355encoding the heavy chain variable region of SEQ ID NO:347;polynucleotides encoding the complementarity-determining regions (SEQ IDNO:356; SEQ ID NO:357; and SEQ ID NO:358) of the light chain variableregion of SEQ ID NO:346; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:359; SEQ ID NO:360; andSEQ ID NO:361) of the heavy chain variable region of SEQ ID NO:347.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:362:

(SEQ ID NO: 370) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCTCAAGTGCTGACCCAGACTCCATCCTCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAATTGCCAGGCCAGTCAGAGTGTTTATCAGAACAACTACTTATCCTGGTTTCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGGTGCGGCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGACCTGGAGTGTGACGATGCTGCCACTTACTACTGTGCAGGCGCTT ATAGGGATGTGGATTCT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:363:

(SEQ ID NO: 371) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGTTGGAGGAGTCCGGGGGAGACCTGGTCAAGCCTGGGGCATCCCTGACACTCACCTGCACAGCCTCTGGATTCTCCTTTACTAGTACCTACTACATCTACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGTATTGATGCTGGTAGTAGTGGTAGCACTTACTACGCGACCTGGGTGAATGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGACTCTGCAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTCTGTGCGAAATGGGATTATGGTGGTAATGTTGGTTGGGGTTATGACTTG.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:372; SEQ ID NO:373; and SEQ ID NO:374 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:362.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:375; SEQ ID NO:376; and SEQ ID NO:377 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:363.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:370 encoding the light chainvariable region of SEQ ID NO:362; the polynucleotide SEQ ID NO:371encoding the heavy chain variable region of SEQ ID NO:363;polynucleotides encoding the complementarity-determining regions (SEQ IDNO:372; SEQ ID NO:373; and SEQ ID NO:374) of the light chain variableregion of SEQ ID NO:362; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:375; SEQ ID NO:376; andSEQ ID NO:377) of the heavy chain variable region of SEQ ID NO:363.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:378:

(SEQ ID NO: 386) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGCATTCGAATTGACCCAGACTCCATCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGCATTAGTAGTTACTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGTTCCTGATCTACAGGGCGTCCACTCTGGCATCTGGGGTCCCATCGCGATTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAAAGCTATTATGATA GTGTTTCAAATCCT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:379:

(SEQ ID NO: 387) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGTTGGAGGAGTCCGGGGGAGACCTGGTCAAGCCTGAGGGATCCCTGACACTCACCTGCAAAGCCTCTGGACTCGACCTCGGTACCTACTGGTTCATGTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCTTGTATTTATACTGGTAGTAGTGGTTCCACTTTCTACGCGAGCTGGGTGAATGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGACTCTGCAAATGACCAGTCTGACAGCCGCGGACACGGCCACTTATTTTTGTGCGAGAGGTTATAGTGGTTATGGTTATTTTAAGTTG.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:388; SEQ ID NO:389; and SEQ ID NO:390 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:378.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:391; SEQ ID NO:392; and SEQ ID NO:393 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:379.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:386 encoding the light chainvariable region of SEQ ID NO:378; the polynucleotide SEQ ID NO:387encoding the heavy chain variable region of SEQ ID NO:379;polynucleotides encoding the complementarity-determining regions (SEQ IDNO:388; SEQ ID NO:389; and SEQ ID NO:390) of the light chain variableregion of SEQ ID NO:378; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:391; SEQ ID NO:392; andSEQ ID NO:393) of the heavy chain variable region of SEQ ID NO:379.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:394:

(SEQ ID NO: 402) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGTCACATTTGCCATCGAAATGACCCAGAGTCCATTCTCCGTGTCTGCAGCTGTGGGAGGCACAGTCAGCATCAGTTGCCAGGCCAGTCAGAGTGTTTATAAGAACAACCAATTATCCTGGTATCAGCAGAAATCAGGGCAGCCTCCCAAGCTCCTGATCTATGGTGCATCGGCTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACGTGCAGTGTGACGATGCTGCCACTTACTACTGTGCAGGCGCTATTACTGGTAGTATTGATACGGATGGT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:395:

(SEQ ID NO: 403) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGTTGGAGGAGTCCGGGGGAGACCTGGTCAAGCCTGGGGCATCCCTGACACTCACCTGCACAACTTCTGGATTCTCCTTCAGTAGCAGCTACTTCATTTGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGATCGCATGCATTTATGGTGGTGATGGCAGCACATACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGTCGACCACGGTGACGCTGCAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTCTGTGCGAGAGAATGGGCATATAGTCAAGGTTATTTTGGTGCTTTTGATCTC.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:404; SEQ ID NO:405; and SEQ ID NO:406 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:394.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:407; SEQ ID NO:408; and SEQ ID NO:409 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:395.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:402 encoding the light chainvariable region of SEQ ID NO:394; the polynucleotide SEQ ID NO:403encoding the heavy chain variable region of SEQ ID NO:395;polynucleotides encoding the complementarity-determining regions (SEQ IDNO:404; SEQ ID NO:405; and SEQ ID NO:406) of the light chain variableregion of SEQ ID NO:394; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:407; SEQ ID NO:408; andSEQ ID NO:409) of the heavy chain variable region of SEQ ID NO:395.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:410:

(SEQ ID NO: 418) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGATGTTGTGATGACCCAGACTCCAGCCTCCGTGGAGGCAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTGAGGATATTAGTAGCTACTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGCTGCATCCAATCTGGAATCTGGGGTCTCATCGCGATTCAAAGGCAGTGGATCTGGGACAGAGTACACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACCTATTACTGTCAATGTACTTATGGTACTATTTCTATTAGTGATGGTAATGCT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:411:

(SEQ ID NO: 419) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAATGTCAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGTCTCTGGATTCTCCCTCAGTAGCTACTTCATGACCTGGGTCCGCCAGGCTCCAGGGGAGGGGCTGGAATACATCGGATTCATTAATCCTGGTGGTAGCGCTTACTACGCGAGCTGGGTGAAAGGCCGATTCACCATCTCCAAGTCCTCGACCACGGTAGATCTGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGGGTTCTGATTGTTTCTTATGGAGCCTTTACCATC.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:420; SEQ ID NO:421; and SEQ ID NO:422 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:410.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:423; SEQ ID NO:424; and SEQ ID NO:425 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:411.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:418 encoding the light chainvariable region of SEQ ID NO:410; the polynucleotide SEQ ID NO:419encoding the heavy chain variable region of SEQ ID NO:411;polynucleotides encoding the complementarity-determining regions (SEQ IDNO:420; SEQ ID NO:421; and SEQ ID NO:422) of the light chain variableregion of SEQ ID NO:410; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:423; SEQ ID NO:424; andSEQ ID NO:425) of the heavy chain variable region of SEQ ID NO:411.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:426:

(SEQ ID NO: 434) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGATGTTGTGATGACCCAGACTCCAGCCTCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTGAGGACATTGAAAGCTATCTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGGTGCATCCAATCTGGAATCTGGGGTCTCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTATTGTCAATGCACTTATGGTATTATTAGTATTAGTGATGGTAATGCT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:427:

(SEQ ID NO: 435) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGTGTCTGGATTCTCCCTCAGTAGCTACTTCATGACCTGGGTCCGCCAGGCTCCAGGGGAGGGGCTGGAATACATCGGATTCATGAATACTGGTGATAACGCATACTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGGGTTCTTGTTGTTGCTTATGGAGCCTTTAACATC.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:436; SEQ ID NO:437; and SEQ ID NO:438 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:426.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:439; SEQ ID NO:440; and SEQ ID NO:441 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:427.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:434 encoding the light chainvariable region of SEQ ID NO:426; the polynucleotide SEQ ID NO:435encoding the heavy chain variable region of SEQ ID NO:427;polynucleotides encoding the complementarity-determining regions (SEQ IDNO:436; SEQ ID NO:437; and SEQ ID NO:438) of the light chain variableregion of SEQ ID NO:426; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:439; SEQ ID NO:440; andSEQ ID NO:441) of the heavy chain variable region of SEQ ID NO:427.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:442:

(SEQ ID NO: 450) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCCGCCGTGCTGACCCAGACTCCATCTCCCGTGTCTGAACCTGTGGGAGGCACAGTCAGCATCAGTTGCCAGTCCAGTAAGAGTGTTATGAATAACAACTACTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGGTGCATCCAATCTGGCATCTGGGGTCCCATCACGGTTCAGCGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGACGTGCAGTGTGACGATGCTGCCACTTACTACTGTCAAGGCGGTTATACTGGTTATAGTGATCATGGGACT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:443:

(SEQ ID NO: 451) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCAAGCCTGACGAAACCCTGACACTCACCTGCACAGTCTCTGGAATCGACCTCAGTAGCTATCCAATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGATTCATTAATACTGGTGGTACCATAGTCTACGCGAGCTGGGCAAAAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGAAAATGACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGGCAGTTATGTTTCATCTGGTTATGCCTACTATTTTAATGTC.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:452; SEQ ID NO:453; and SEQ ID NO:454 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:442.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:455; SEQ ID NO:456; and SEQ ID NO:457 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:443.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:450 encoding the light chainvariable region of SEQ ID NO:442; the polynucleotide SEQ ID NO:451encoding the heavy chain variable region of SEQ ID NO:443;polynucleotides encoding the complementarity-determining regions (SEQ IDNO:452; SEQ ID NO:453; and SEQ ID NO:454) of the light chain variableregion of SEQ ID NO:442; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:455; SEQ ID NO:456; andSEQ ID NO:457) of the heavy chain variable region of SEQ ID NO:443.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:458:

(SEQ ID NO: 466) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCCGCCGTGCTGACCCAGACTCCATCTCCCGTGTCTGCAGCTGTGGGAGGCACAGTCAGCATCAGTTGCCAGTCCAGTCAGAGTGTTTATAATAACAACTGGTTATCCTGGTTTCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACAAGGCATCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGACGTGCAGTGTGACGATGTTGCCACTTACTACTGTGCGGGCGGTTATCT TGATAGTGTTATT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:459:

(SEQ ID NO: 467) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGTCTCTGGATTCTCCCTCAGTACCTATTCAATAAACTGGGTCCGCCAGGCTCCAGGGAAGGGCCTGGAATGGATCGGAATCATTGCTAATAGTGGTACCACATTCTACGCGAACTGGGCGAAAGGCCGATTCACCGTCTCCAAAACCTCGACCACGGTGGATCTGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGAGAGTGGAATGTACAATGAATATGGTAAATTTAACATC.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:468; SEQ ID NO:469; and SEQ ID NO:470 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:458.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:471; SEQ ID NO:472; and SEQ ID NO:473 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:459.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:466 encoding the light chainvariable region of SEQ ID NO:458; the polynucleotide SEQ ID NO:467encoding the heavy chain variable region of SEQ ID NO:459;polynucleotides encoding the complementarity-determining regions (SEQ IDNO:468; SEQ ID NO:469; and SEQ ID NO:470) of the light chain variableregion of SEQ ID NO:458; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:471; SEQ ID NO:472; andSEQ ID NO:473) of the heavy chain variable region of SEQ ID NO:459.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:474:

(SEQ ID NO: 482) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGCCTCTGATATGACCCAGACTCCATCCTCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAATTGCCAGGCCAGTGAGAACATTTATAGCTTTTTGGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTTCAAGGCTTCCACTCTGGCATCTGGGGTCTCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGACCTGGAGTGTGACGATGCTGCCACTTACTACTGTCAACAGGGTGCTACTGTGTA TGATATTGATAATAAT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:475:

(SEQ ID NO: 483) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGTTTCTGGAATCGACCTCAGTGCCTATGCAATGATCTGGGTCCGCCAGGCTCCAGGGGAGGGGCTGGAATGGATCACAATCATTTATCCTAATGGTATCACATACTACGCGAACTGGGCGAAAGGCCGATTCACCGTCTCCAAAACCTCGACCGCGATGGATCTGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGATGCAGAAAGTAGTAAGAATGCTTATTGGGGCTACTTTAACGTC.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:484; SEQ ID NO:485; and SEQ ID NO:486 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:474.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:487; SEQ ID NO:488; and SEQ ID NO:489 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:475.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:482 encoding the light chainvariable region of SEQ ID NO:474; the polynucleotide SEQ ID NO:483encoding the heavy chain variable region of SEQ ID NO:475;polynucleotides encoding the complementarity-determining regions (SEQ IDNO:484; SEQ ID NO:485; and SEQ ID NO:486) of the light chain variableregion of SEQ ID NO:474; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:487; SEQ ID NO:488; andSEQ ID NO:489) of the heavy chain variable region of SEQ ID NO:475.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:490:

(SEQ ID NO: 498) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGCCTCTGATATGACCCAGACTCCATCCTCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAATTGCCAGGCCAGTGAGAACATTTATAGCTTTTTGGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTTCAGGGCTTCCACTCTGGCATCTGGGGTCTCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGACCTGGAGTGTGACGATGCTGCCACTTACTACTGTCAACAGGGTGCTACTGTGTA TGATATTGATAATAAT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:491:

(SEQ ID NO: 499) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGTTTCTGGAATCGACCTCAGTGCCTATGCAATGATCTGGGTCCGCCAGGCTCCAGGGGAGGGGCTGGAATGGATCACAATCATTTATCCTAATGGTATCACATACTACGCGAACTGGGCGAAAGGCCGATTCACCGTCTCCAAAACCTCGACCGCGATGGATCTGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGATGCAGAAAGTAGTAAGAATGCTTATTGGGGCTACTTTAACGTC.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:500; SEQ ID NO:501; and SEQ ID NO:502 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:490.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:503; SEQ ID NO:504; and SEQ ID NO:505 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:491.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:498 encoding the light chainvariable region of SEQ ID NO:490; the polynucleotide SEQ ID NO:499encoding the heavy chain variable region of SEQ ID NO:491;polynucleotides encoding the complementarity-determining regions (SEQ IDNO:500; SEQ ID NO:501; and SEQ ID NO:502) of the light chain variableregion of SEQ ID NO:490; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:503; SEQ ID NO:504; andSEQ ID NO:505) of the heavy chain variable region of SEQ ID NO:491.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:506:

(SEQ ID NO: 514) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCCATTGAAATGACCCAGACTCCATCCCCCGTGTCTGCCGCTGTGGGAGGCACAGTCACCATCAATTGCCAGGCCAGTGAGAGTGTTTTTAATAATATGTTATCCTGGTATCAGCAGAAACCAGGGCACTCTCCTAAGCTCCTGATCTATGATGCATCCGATCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGTGGCGTGGAGTGTGACGATGCTGCCACTTACTATTGTGCAGGGTATAAAAGTGATAGTAATGATGGCGATAATGTT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:507:

(SEQ ID NO: 515) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGTCTCTGGATTCTCCCTCAACAGGAATTCAATAACCTGGGTCCGCCAGGCTCCAGGGGAGGGGCTGGAATGGATCGGAATCATTACTGGTAGTGGTAGAACGTACTACGCGAACTGGGCAAAAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGAAAATGACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGGCCATCCTGG TCTTGGTAGTGGTAACATC.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:516; SEQ ID NO:517; and SEQ ID NO:518 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:506.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:519; SEQ ID NO:520; and SEQ ID NO:521 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:507.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:514 encoding the light chainvariable region of SEQ ID NO:506; the polynucleotide SEQ ID NO:515encoding the heavy chain variable region of SEQ ID NO:507;polynucleotides encoding the complementarity-determining regions (SEQ IDNO:516; SEQ ID NO:517; and SEQ ID NO:518) of the light chain variableregion of SEQ ID NO:506; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:519; SEQ ID NO:520; andSEQ ID NO:521) of the heavy chain variable region of SEQ ID NO:507.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:522:

(SEQ ID NO: 530) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCGCAAGTGCTGACCCAGACTGCATCGTCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAATTGCCAGTCCAGTCAGAGTGTTTATAATAACTACTTATCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATACTGCATCCAGCCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGAAGTGCAGTGTGACGATGCTGCCACTTACTACTGTCAAGGCTATT ATAGTGGTCCTATAATTACT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:523:

(SEQ ID NO: 531) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGCCTCTGGATTCTCCCTCAATAACTACTACATACAATGGGTCCGCCAGGCTCCAGGGGAGGGGCTGGAATGGATCGGGATCATTTATGCTGGTGGTAGCGCATACTACGCGACCTGGGCAAACGGCCGATTCACCATCGCCAAAACCTCGTCGACCACGGTGGATCTGAAGATGACCAGTCTGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGGGACATTTGATGGTTATGAGTTG.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:532; SEQ ID NO:533; and SEQ ID NO:534 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:522.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:535; SEQ ID NO:536; and SEQ ID NO:537 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:523.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:530 encoding the light chainvariable region of SEQ ID NO:522; the polynucleotide SEQ ID NO:531encoding the heavy chain variable region of SEQ ID NO:523;polynucleotides encoding the complementarity-determining regions (SEQ IDNO:532; SEQ ID NO:533; and SEQ ID NO:534) of the light chain variableregion of SEQ ID NO:522; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:535; SEQ ID NO:536; andSEQ ID NO:537) of the heavy chain variable region of SEQ ID NO:523.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:538:

(SEQ ID NO: 546) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCCCAAGTGCTGACCCAGACTCCATCCCCTGTGTCTGTCCCTGTGGGAGACACAGTCACCATCAGTTGCCAGTCCAGTGAGAGCGTTTATAGTAATAACCTCTTATCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACAGGGCATCCAATCTGGCATCTGGTGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGGCGCACAGTGTGACGATGCTGCCACTTACTACTGTCAAGGCTATTATAGTGGTGTCATTAATAGT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:539:

(SEQ ID NO: 547) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGTGTCTGGATTCTCCCTCAGTAGCTACTTCATGAGCTGGGTCCGCCAGGCTCCAGGGGAGGGGCTGGAATACATCGGATTCATTAATCCTGGTGGTAGCGCATACTACGCGAGCTGGGCGAGTGGCCGACTCACCATCTCCAAAACCTCGACCACGGTAGATCTGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGGATTCTTATTGTTTCTTATGGAGCCTTTACCATC.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:548; SEQ ID NO:549; and SEQ ID NO:550 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:538.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:551; SEQ ID NO:552; and SEQ ID NO:553 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:539.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:546 encoding the light chainvariable region of SEQ ID NO:538; the polynucleotide SEQ ID NO:547encoding the heavy chain variable region of SEQ ID NO:539;polynucleotides encoding the complementarity-determining regions (SEQ IDNO:548; SEQ ID NO:549; and SEQ ID NO:550) of the light chain variableregion of SEQ ID NO:538; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:551; SEQ ID NO:552; andSEQ ID NO:553) of the heavy chain variable region of SEQ ID NO:539.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:554:

(SEQ ID NO: 562) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGCCTATGATATGACCCAGACTCCAGCCTCTGTGGAGGTAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCACTGAGAGCATTGGCAATGAGTTATCCTGGTATCAGCAGAAACCAGGGCAGGCTCCCAAGCTCCTGATCTATTCTGCATCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCACCGGCGTGGAGTGTGATGATGCTGCCACTTACTACTGTCAACAGGGTTATAGTAGTGCTAATATTGATAATGCT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:555:

(SEQ ID NO: 563) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACCGTCTCTGGATTCTCCCTCAGTAAGTACTACATGAGCTGGGTCCGCCAGGCTCCAGAGAAGGGGCTGAAATACATCGGATACATTGATAGTACTACTGTTAATACATACTACGCGACCTGGGCGAGAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGAAGATCACCAGTCCGACAAGTGAGGACACGGCCACCTATTTCTGTGCCAGAGGAAGTACTTATTTTACTGATGGAGGCCATCGGTTGGATCTC.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:564; SEQ ID NO:565; and SEQ ID NO:566 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:554.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:567; SEQ ID NO:568; and SEQ ID NO:569 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:555.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:562 encoding the light chainvariable region of SEQ ID NO:554; the polynucleotide SEQ ID NO:563encoding the heavy chain variable region of SEQ ID NO:555;polynucleotides encoding the complementarity-determining regions (SEQ IDNO:564; SEQ ID NO:565; and SEQ ID NO:566) of the light chain variableregion of SEQ ID NO:554; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:567; SEQ ID NO:568; andSEQ ID NO:569) of the heavy chain variable region of SEQ ID NO:555.

The invention is further directed to polynucleotides encodingpolypeptides of the antibodies having binding specificity to IL-6. Inone embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable light chain polypeptide sequence of SEQID NO:570:

(SEQ ID NO: 578) ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGCCTATGATATGACCCAGACTCCAGCCTCTGTGGAGGTAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCACTGAGAGCATTGGCAATGAGTTATCCTGGTATCAGCAGAAACCAGGGCAGGCTCCCAAGCTCCTGATCTATTCTGCATCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCACCGGCGTGGAGTGTGATGATGCTGCCACTTACTACTGTCAACAGGGTTATAGTAGTGCTAATATTGATAATGCT

In another embodiment of the invention, polynucleotides of the inventioncomprise, or alternatively consist of, the following polynucleotidesequence encoding the variable heavy chain polypeptide sequence of SEQID NO:571:

(SEQ ID NO: 579) ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTAACGCCTGGGACACCCCTGACACTCACCTGCACAGTCTCTGGATTCTCCCTCAGTACCTACAACATGGGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGAAGTATTACTATTGATGGTCGCACATACTACGCGAGCTGGGCGAAAGGCCGATTCACCGTCTCCAAAAGCTCGACCACGGTGGATCTGAAAATGACCAGTCTGACAACCGGGGACACGGCCACCTATTTCTGTGCCAGGATTCTTATTGTTTCTTATGGGGCCTTTACCATC.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:580; SEQ ID NO:581; and SEQ ID NO:582 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the light chain variable sequence of SEQ IDNO:570.

In a further embodiment of the invention, polynucleotides encodingfragments of the antibody having binding specificity to IL-6 comprise,or alternatively consist of, one or more of the polynucleotide sequencesof SEQ ID NO:583; SEQ ID NO:584; and SEQ ID NO:585 which correspond topolynucleotides encoding the complementarity-determining regions (CDRs,or hypervariable regions) of the heavy chain variable sequence of SEQ IDNO:571.

The invention also contemplates polynucleotide sequences including oneor more of the polynucleotide sequences encoding antibody fragmentsdescribed herein. In one embodiment of the invention, polynucleotidesencoding fragments of the antibody having binding specificity to IL-6comprise, or alternatively consist of, one, two, three or more,including all of the following polynucleotides encoding antibodyfragments: the polynucleotide SEQ ID NO:578 encoding the light chainvariable region of SEQ ID NO:570; the polynucleotide SEQ ID NO:579encoding the heavy chain variable region of SEQ ID NO:571;polynucleotides encoding the complementarity-determining regions (SEQ IDNO:580; SEQ ID NO:581; and SEQ ID NO:582) of the light chain variableregion of SEQ ID NO:570; and polynucleotides encoding thecomplementarity-determining regions (SEQ ID NO:583; SEQ ID NO:584; andSEQ ID NO:585) of the heavy chain variable region of SEQ ID NO:571.

In another embodiment of the invention, polynucleotides of the inventionfurther comprise, the following polynucleotide sequence encoding thekappa constant light chain sequence of SEQ ID NO:586:

(SEQ ID NO: 587) GTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAG AGCTTCAACAGGGGAGAGTGT.

In another embodiment of the invention, polynucleotides of the inventionfurther comprise, the following polynucleotide sequence encoding thegamma-1 constant heavy chain polypeptide sequence of SEQ ID NO:588:

(SEQ ID NO: 589) GCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACGCCAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTC TCCGGGTAAA.

In one embodiment, the invention is directed to an isolatedpolynucleotide comprising a polynucleotide encoding an anti-IL-6 V_(H)antibody amino acid sequence selected from SEQ ID NO:3, 18, 19, 652,653, 654, 655, 656, 657, 658, 661, 664, 665, 657, 658, 704, 708, 22,668, 38, 672, 54, 676, 70, 680, 86, 684, 102, 117, 118, 688, 691, 692,123, 139, 155, 171, 187, 203, 219, 235, 251, 267, 283, 299, 315, 331,347, 363, 379, 395, 411, 427, 443, 459, 475, 491, 507, 523, 539, 555 andSEQ ID NO:571, or those contained in FIG. 15 or encoding a variantthereof wherein at least one framework residue (FR residue) has beensubstituted with an amino acid present at the corresponding position ina rabbit anti-IL-6 antibody V_(H) polypeptide or a conservative aminoacid substitution. In addition, the invention specifically encompasseshumanized anti-Il-6 antibodies or humanized antibody binding fragmentsand nucleic acid sequences encoding the foregoing comprising thehumanized variable heavy chain and/or light chain polypeptides depictedin the sequences contained in FIG. 15 or variants thereof wherein one ormore framework or CDR residues may be modified. Preferably, if anymodifications are introduced they will not affect adversely the bindingaffinity of the resulting humanized anti-IL-6 antibody or fragment.

In another embodiment, the invention is directed to an isolatedpolynucleotide comprising the polynucleotide sequence encoding ananti-IL-6 V_(L) antibody amino acid sequence of SEQ ID NO:2, 20, 709,647, 648, 649, 650, 651, 660, 666, 699, 702, 706, 21, 667, 37, 671, 53,675, 69, 679, 85, 683, 101, 119, 687, 693, 122, 138, 154, 170, 186, 202,218, 234, 250, 266, 282, 298, 314, 330, 346, 362, 378, 394, 410, 426,442, 458, 474, 490, 506, 522, 538, 554 and SEQ ID NO:570 or othersdepicted in FIG. 15 or another polynucleotide encoding a variant thereofwherein at least one framework residue (FR residue) has been substitutedwith an amino acid present at the corresponding position in a rabbitanti-IL-6 antibody V_(L) polypeptide or a conservative amino acidsubstitution.

In yet another embodiment, the invention is directed to one or moreheterologous polynucleotides comprising a sequence encoding thepolypeptides contained in SEQ ID NO: 2, 20, 647, 648, 649, 650, 651,660, 666, 699, 702, 706, or 709 and SEQ ID NO: 3, 18, 19, 652, 653, 654,655, 656, 657, 661, 664, 665, 657, 658, 704, or 708; SEQ ID NO:21 or SEQID NO:667 and SEQ ID NO:22; SEQ ID NO:668; SEQ ID NO:37 or SEQ ID NO:671and SEQ ID NO:38 or SEQ ID NO:672; SEQ ID NO:53 or SEQ ID NO:675 and SEQID NO:54 or SEQ ID NO:676; SEQ ID NO:69 or SEQ ID NO:679 and SEQ IDNO:70 or SEQ ID NO:680; SEQ ID NO:85 or SEQ ID NO:683 and SEQ ID NO:86or SEQ ID NO:684; SEQ ID NO: 101, 119, 687, or 693 and SEQ ID NO: 102,117, 118, 688, 691, or 692 SEQ ID NO:122 and SEQ ID NO:123; SEQ IDNO:138 and SEQ ID NO:139; SEQ ID NO:154 and SEQ ID NO:155; SEQ ID NO:170and SEQ ID NO:171; SEQ ID NO:186 and SEQ ID NO:187; SEQ ID NO:202 andSEQ ID NO:203; SEQ ID NO:218 and SEQ ID NO:219; SEQ ID NO:234 and SEQ IDNO:235; SEQ ID NO:250 and SEQ ID NO:251; SEQ ID NO:266 and SEQ IDNO:267; SEQ ID NO:282 and SEQ ID NO:283; SEQ ID NO:298 and SEQ IDNO:299; SEQ ID NO:314 and SEQ ID NO:315; SEQ ID NO:330 and SEQ IDNO:331; SEQ ID NO:346 and SEQ ID NO:347; SEQ ID NO:362 and SEQ IDNO:363; SEQ ID NO:378 and SEQ ID NO:379; SEQ ID NO:394 and SEQ IDNO:395; SEQ ID NO:410 and SEQ ID NO:411; SEQ ID NO:426 and SEQ IDNO:427; SEQ ID NO:442 and SEQ ID NO:443; SEQ ID NO:458 and SEQ IDNO:459; SEQ ID NO:474 and SEQ ID NO:475; SEQ ID NO:490 and SEQ IDNO:491; SEQ ID NO:506 and SEQ ID NO:507; SEQ ID NO:522 and SEQ IDNO:523; SEQ ID NO:538 and SEQ ID NO:539; SEQ ID NO:554 and SEQ IDNO:555; or SEQ ID NO:570 and SEQ ID NO:571.

In another embodiment, the invention is directed to an isolatedpolynucleotide that expresses a polypeptide containing at least one CDRpolypeptide derived from an anti-IL-6 antibody wherein said expressedpolypeptide alone specifically binds IL-6 or specifically binds IL-6when expressed in association with another polynucleotide sequence thatexpresses a polypeptide containing at least one CDR polypeptide derivedfrom an anti-IL-6 antibody wherein said at least one CDR is selectedfrom those contained in the V_(L) or V_(H) polypeptides contained in SEQID NO: 3, 18, 19, 652, 653, 654, 655, 656, 657, 658, 661, 664, 665, 657,658, 704, 708, 22, 668, 38, 672, 54, 676, 70, 680, 86, 684, 102, 117,118, 688, 691, 692, 123, 139, 155, 171, 187, 203, 219, 235, 251, 267,283, 299, 315, 331, 347, 363, 379, 395, 411, 427, 443, 459, 475, 491,507, 523, 539, 555; 571; 2, 20, 647, 648, 649, 650, 651, 709, 660, 666,699, 702, 706, 21, 667, 37, 671, 53, 675, 69, 679, 85, 683, 101, 119,687, 693, 122, 138, 154, 170, 186, 202, 218, 234, 250, 266, 282, 298,314, 330, 346, 362, 378, 394, 410, 426, 442, 458, 474, 490, 506, 522,538, 554 and SEQ ID NO:570.

In particular the invention embraces polynucleotides and vectorscontaining encoding a variable heavy and/or variable light regionselected from those depicted in FIG. 15.

Host cells and vectors comprising said polynucleotides are alsocontemplated.

The invention further contemplates vectors comprising the polynucleotidesequences encoding the variable heavy and light chain polypeptidesequences, as well as the individual complementarity determining regions(CDRs, or hypervariable regions) set forth herein, as well as host cellscomprising said sequences. In one embodiment of the invention, the hostcell is a yeast cell. In another embodiment of the invention, the yeasthost cell belongs to the genus Pichia.

Anti-IL-6 Activity

As stated previously, IL-6 is a member of a family of cytokines thatpromote cellular responses through a receptor complex consisting of atleast one subunit of the signal-transducing glycoprotein gp130 and theIL-6 receptor (IL-6R). The IL-6R may also be present in a soluble form(sIL-6R). IL-6 binds to IL-6R, which then dimerizes thesignal-transducing receptor gp130.

It is believed that the anti-IL-6 antibodies of the invention, or IL-6binding fragments thereof, are useful by exhibiting anti-IL-6 activity.In one non-limiting embodiment of the invention, the anti-IL-6antibodies of the invention, or IL-6 binding fragments thereof, exhibitanti-IL-6 activity by binding to IL-6 which may be soluble IL-6 or cellsurface expressed IL-6 and/or may prevent or inhibit the binding of IL-6to IL-6R and/or activation (dimerization) of the gp130signal-transducing glycoprotein and the formation of IL-6/IL-6R/gp130multimers and the biological effects of any of the foregoing. Thesubject IL-6 antibodies may possess different antagonistic activitiesbased on where (i.e., epitope) the particular antibody binds IL-6 and/orhow it affects the formation of the foregoing IL-6 complexes and/ormultimers and the biological effects thereof. Consequently, differentIL-6 antibodies according to the invention e.g., may be better suitedfor preventing or treating conditions involving the formation andaccumulation of substantial soluble IL-6 such as rheumatoid arthritiswhereas other antibodies may be favored in treatments wherein theprevention of IL-6/IL-6R/gp130 or IL-6/IL-6R/gp130 multimers is adesired therapeutic outcome. This can be determined in binding and otherassays.

The anti-IL-6 activity of the anti-IL-6 antibody of the presentinvention, and fragments thereof having binding specificity to IL-6, mayalso be described by their strength of binding or their affinity forIL-6. This also may affect their therapeutic properties. In oneembodiment of the invention, the anti-IL-6 antibodies of the presentinvention, and fragments thereof having binding specificity to IL-6,bind to IL-6 with a dissociation constant (K_(D)) of less than or equalto 5×10⁻⁷, 10⁻⁷, 5×10⁻⁸, 10⁻⁸, 5×10⁻⁹, 10⁻⁹, 5×10⁻¹⁰, 10⁻¹⁰, 5×10⁻¹¹,10⁻¹¹, 5×10⁻¹², 10⁻¹², 5×10⁻¹³, 10⁻¹³, 5×10⁻¹⁴, 10⁻¹⁴, 5×10⁻¹⁵ or 10⁻¹⁵.Preferably, the anti-IL-6 antibodies and fragments thereof bind IL-6with a dissociation constant of less than or equal to 5×10⁻¹⁰.

In another embodiment of the invention, the anti-IL-6 activity of theanti-IL-6 antibodies of the present invention, and fragments thereofhaving binding specificity to IL-6, bind to IL-6 with an off-rate ofless than or equal to 10⁻⁴ S⁻¹, 5×10⁻⁵ S⁻¹, 10⁻⁵ S⁻¹, 5×10⁻⁶ S⁻¹, 10⁻⁶S⁻¹, 5×10⁻⁷ S⁻¹, or 10⁻⁷ S⁻¹. In one embodiment of the invention, theanti-IL-6 antibodies of the invention, and fragments thereof havingbinding specificity to IL-6, bind to a linear or conformational IL-6epitope.

In a further embodiment of the invention, the anti-IL-6 activity of theanti-IL-6 antibodies of the present invention, and fragments thereofhaving binding specificity to IL-6, exhibit anti-IL-6 activity byameliorating or reducing the symptoms of, or alternatively treating, orpreventing, diseases and disorders associated with IL-6. Non-limitingexamples of diseases and disorders associated with IL-6 are set forthinfra. As noted cancer-related fatigue, cachexia and rheumatoidarthritis are preferred indications for the subject IL-6 antibodies.

In another embodiment of the invention, the anti-IL-6 antibodiesdescribed herein, or IL-6 binding fragments thereof, do not have bindingspecificity for IL-6R or the gp-130 signal-transducing glycoprotein.

B-Cell Screening and Isolation

In one embodiment, the present invention provides methods of isolating aclonal population of antigen-specific B cells that may be used forisolating at least one antigen-specific cell. As described andexemplified infra, these methods contain a series of culture andselection steps that can be used separately, in combination,sequentially, repetitively, or periodically. Preferably, these methodsare used for isolating at least one antigen-specific cell, which can beused to produce a monoclonal antibody, which is specific to a desiredantigen, or a nucleic acid sequence corresponding to such an antibody.

In one embodiment, the present invention provides a method comprisingthe steps of:

a. preparing a cell population comprising at least one antigen-specificB cell;

b. enriching the cell population, e.g., by chromatography, to form anenriched cell population comprising at least one antigen-specific Bcell;

c. isolating a single B cell from the enriched B cell population; and

d. determining whether the single B cell produces an antibody specificto the antigen.

In another embodiment, the present invention provides an improvement toa method of isolating a single, antibody-producing B cell, theimprovement comprising enriching a B cell population obtained from ahost that has been immunized or naturally exposed to an antigen, whereinthe enriching step precedes any selection steps, comprises at least oneculturing step, and results in a clonal population of B cells thatproduces a single monoclonal antibody specific to said antigen.

Throughout this application, a “clonal population of B cells” refers toa population of B cells that only secrete a single antibody specific toa desired antigen. That is to say that these cells produce only one typeof monoclonal antibody specific to the desired antigen.

In the present application, “enriching” a cell population cells meansincreasing the frequency of desired cells, typically antigen-specificcells, contained in a mixed cell population, e.g., a B cell-containingisolate derived from a host that is immunized against a desired antigen.Thus, an enriched cell population encompasses a cell population having ahigher frequency of antigen-specific cells as a result of an enrichmentstep, but this population of cells may contain and produce differentantibodies.

The general term “cell population” encompasses pre- and apost-enrichment cell populations, keeping in mind that when multipleenrichment steps are performed, a cell population can be both pre- andpost-enrichment. For example, in one embodiment, the present inventionprovides a method:

a. harvesting a cell population from an immunized host to obtain aharvested cell population;

b. creating at least one single cell suspension from the harvested cellpopulation;

c. enriching at least one single cell suspension to form a firstenriched cell population;

d. enriching the first enriched cell population to form a secondenriched cell population;

e. enriching the second enriched cell population to form a thirdenriched cell population; and

f. selecting an antibody produced by an antigen-specific cell of thethird enriched cell population.

Each cell population may be used directly in the next step, or it can bepartially or wholly frozen for long- or short-term storage or for latersteps. Also, cells from a cell population can be individually suspendedto yield single cell suspensions. The single cell suspension can beenriched, such that a single cell suspension serves as thepre-enrichment cell population. Then, one or more antigen-specificsingle cell suspensions together form the enriched cell population; theantigen-specific single cell suspensions can be grouped together, e.g.,re-plated for further analysis and/or antibody production.

In one embodiment, the present invention provides a method of enrichinga cell population to yield an enriched cell population having anantigen-specific cell frequency that is about 50% to about 100%, orincrements therein. Preferably, the enriched cell population has anantigen-specific cell frequency greater than or equal to about 50%, 60%,70%, 75%, 80%, 90%, 95%, 99%, or 100%.

In another embodiment, the present invention provides a method ofenriching a cell population whereby the frequency of antigen-specificcells is increased by at least about 2-fold, 5-fold, 10-fold, 20-fold,50-fold, 100-fold, or increments therein.

Throughout this application, the term “increment” is used to define anumerical value in varying degrees of precision, e.g., to the nearest10, 1, 0.1, 0.01, etc. The increment can be rounded to any measurabledegree of precision, and the increment need not be rounded to the samedegree of precision on both sides of a range. For example, the range 1to 100 or increments therein includes ranges such as 20 to 80, 5 to 50,and 0.4 to 98. When a range is open-ended, e.g., a range of less than100, increments therein means increments between 100 and the measurablelimit. For example, less than 100 or increments therein means 0 to 100or increments therein unless the feature, e.g., temperature, is notlimited by 0.

Antigen-specificity can be measured with respect to any antigen. Theantigen can be any substance to which an antibody can bind including,but not limited to, peptides, proteins or fragments thereof;carbohydrates; organic and inorganic molecules; receptors produced byanimal cells, bacterial cells, and viruses; enzymes; agonists andantagonists of biological pathways; hormones; and cytokines. Exemplaryantigens include, but are not limited to, IL-2, IL-4, IL-6, IL-10,IL-12, IL-13, IL-18, IFN-α, IFN-γ, BAFF, CXCL13, IP-10, VEGF, EPO, EGF,HRG, Hepatocyte Growth Factor (HGF) and Hepcidin. Preferred antigensinclude IL-6, IL-13, TNF-α, VEGF-α, Hepatocyte Growth Factor (HGF) andHepcidin. In a method utilizing more than one enrichment step, theantigen used in each enrichment step can be the same as or differentfrom one another. Multiple enrichment steps with the same antigen mayyield a large and/or diverse population of antigen-specific cells;multiple enrichment steps with different antigens may yield an enrichedcell population with cross-specificity to the different antigens.

Enriching a cell population can be performed by any cell-selection meansknown in the art for isolating antigen-specific cells. For example, acell population can be enriched by chromatographic techniques, e.g.,Miltenyi bead or magnetic bead technology. The beads can be directly orindirectly attached to the antigen of interest. In a preferredembodiment, the method of enriching a cell population includes at leastone chromatographic enrichment step.

A cell population can also be enriched by performed by anyantigen-specificity assay technique known in the art, e.g., an ELISAassay or a halo assay. ELISA assays include, but are not limited to,selective antigen immobilization (e.g., biotinylated antigen capture bystreptavidin, avidin, or neutravidin coated plate), non-specific antigenplate coating, and through an antigen build-up strategy (e.g., selectiveantigen capture followed by binding partner addition to generate aheteromeric protein-antigen complex). The antigen can be directly orindirectly attached to a solid matrix or support, e.g., a column. A haloassay comprises contacting the cells with antigen-loaded beads andlabeled anti-host antibody specific to the host used to harvest the Bcells. The label can be, e.g., a fluorophore. In one embodiment, atleast one assay enrichment step is performed on at least one single cellsuspension. In another embodiment, the method of enriching a cellpopulation includes at least one chromatographic enrichment step and atleast one assay enrichment step.

Methods of “enriching” a cell population by size or density are known inthe art. See, e.g., U.S. Pat. No. 5,627,052. These steps can be used inthe present method in addition to enriching the cell population byantigen-specificity.

The cell populations of the present invention contain at least one cellcapable of recognizing an antigen. Antigen-recognizing cells include,but are not limited to, B cells, plasma cells, and progeny thereof. Inone embodiment, the present invention provides a clonal cell populationcontaining a single type of antigen-specific B-cell, i.e., the cellpopulation produces a single monoclonal antibody specific to a desiredantigen.

In such embodiment, it is believed that the clonal antigen-specificpopulation of B cells consists predominantly of antigen-specific,antibody-secreting cells, which are obtained by the novel culture andselection protocol provided herein. Accordingly, the present inventionalso provides methods for obtaining an enriched cell populationcontaining at least one antigen-specific, antibody-secreting cell. Inone embodiment, the present invention provides an enriched cellpopulation containing about 50% to about 100%, or increments therein, orgreater than or equal to about 60%, 70%, 80%, 90%, or 100% ofantigen-specific, antibody-secreting cells.

In one embodiment, the present invention provides a method of isolatinga single B cell by enriching a cell population obtained from a hostbefore any selection steps, e.g., selecting a particular B cell from acell population and/or selecting an antibody produced by a particularcell. The enrichment step can be performed as one, two, three, or moresteps. In one embodiment, a single B cell is isolated from an enrichedcell population before confirming whether the single B cell secretes anantibody with antigen-specificity and/or a desired property.

In one embodiment, a method of enriching a cell population is used in amethod for antibody production and/or selection. Thus, the presentinvention provides a method comprising enriching a cell populationbefore selecting an antibody. The method can include the steps of:preparing a cell population comprising at least one antigen-specificcell, enriching the cell population by isolating at least oneantigen-specific cell to form an enriched cell population, and inducingantibody production from at least one antigen-specific cell. In apreferred embodiment, the enriched cell population contains more thanone antigen-specific cell. In one embodiment, each antigen-specific cellof the enriched population is cultured under conditions that yield aclonal antigen-specific B cell population before isolating an antibodyproducing cell therefrom and/or producing an antibody using said B cell,or a nucleic acid sequence corresponding to such an antibody. Incontrast to prior techniques where antibodies are produced from a cellpopulation with a low frequency of antigen-specific cells, the presentinvention allows antibody selection from among a high frequency ofantigen-specific cells. Because an enrichment step is used prior toantibody selection, the majority of the cells, preferably virtually allof the cells, used for antibody production are antigen-specific. Byproducing antibodies from a population of cells with an increasedfrequency of antigen specificity, the quantity and variety of antibodiesare increased.

In the antibody selection methods of the present invention, an antibodyis preferably selected after an enrichment step and a culture step thatresults in a clonal population of antigen-specific B cells. The methodscan further comprise a step of sequencing a selected antibody orportions thereof from one or more isolated, antigen-specific cells. Anymethod known in the art for sequencing can be employed and can includesequencing the heavy chain, light chain, variable region(s), and/orcomplementarity determining region(s) (CDR).

In addition to the enrichment step, the method for antibody selectioncan also include one or more steps of screening a cell population forantigen recognition and/or antibody functionality. For example, thedesired antibodies may have specific structural features, such asbinding to a particular epitope or mimicry of a particular structure;antagonist or agonist activity; or neutralizing activity, e.g.,inhibiting binding between the antigen and a ligand. In one embodiment,the antibody functionality screen is ligand-dependent. Screening forantibody functionality includes, but is not limited to, an in vitroprotein-protein interaction assay that recreates the natural interactionof the antigen ligand with recombinant receptor protein; and acell-based response that is ligand dependent and easily monitored (e.g.,proliferation response). In one embodiment, the method for antibodyselection includes a step of screening the cell population for antibodyfunctionality by measuring the inhibitory concentration (IC50). In oneembodiment, at least one of the isolated, antigen-specific cellsproduces an antibody having an IC50 of less than about 100, 50, 30, 25,10 μg/mL, or increments therein.

In addition to the enrichment step, the method for antibody selectioncan also include one or more steps of screening a cell population forantibody binding strength. Antibody binding strength can be measured byany method known in the art (e.g., Biacore). In one embodiment, at leastone of the isolated, antigen-specific cells produces an antibody havinga high antigen affinity, e.g., a dissociation constant (Kd) of less thanabout 5×10⁻¹° M−1, preferably about 1×10⁻¹³ to 5×10⁻¹⁰, 1×10⁻¹² to1×10⁻¹⁰, 1×10⁻¹² to 7.5×10⁻¹¹, 1×10⁻¹¹ to 2×10⁻¹¹, about 1.5×10⁻¹¹ orless, or increments therein. In this embodiment, the antibodies are saidto be affinity mature. In a preferred embodiment, the affinity of theantibodies is comparable to or higher than the affinity of any one ofPanorex® (edrecolomab), Rituxan® (rituximab), Herceptin® (traztuzumab),Mylotarg® (gentuzumab), Campath® (alemtuzumab), Zevalin™ (ibritumomab),Erbitux™ (cetuximab), Avastin™ (bevicizumab), Raptiva™ (efalizumab),Remicade® (infliximab), Humira™ (adalimumab), and Xolair™ (omalizumab).Preferably, the affinity of the antibodies is comparable to or higherthan the affinity of Humira™. The affinity of an antibody can also beincreased by known affinity maturation techniques. In one embodiment, atleast one cell population is screened for at least one of, preferablyboth, antibody functionality and antibody binding strength.

In addition to the enrichment step, the method for antibody selectioncan also include one or more steps of screening a cell population forantibody sequence homology, especially human homology. In oneembodiment, at least one of the isolated, antigen-specific cellsproduces an antibody that has a homology to a human antibody of about50% to about 100%, or increments therein, or greater than about 60%,70%, 80%, 85%, 90%, or 95% homologous. The antibodies can be humanizedto increase the homology to a human sequence by techniques known in theart such as CDR grafting or selectivity determining residue grafting(SDR).

In another embodiment, the present invention also provides theantibodies themselves according to any of the embodiments describedabove in terms of IC50, Kd, and/or homology.

The B cell selection protocol disclosed herein has a number of intrinsicadvantages versus other methods for obtaining antibody-secreting B cellsand monoclonal antibodies specific to desired target antigens. Theseadvantages include, but are not restricted to, the following:

First, it has been found that when these selection procedures areutilized with a desired antigen such as IL-6 or TNF-α, the methodsreproducibly result in antigen-specific B cells capable of generatingwhat appears to be a substantially comprehensive complement ofantibodies, i.e., antibodies that bind to the various different epitopesof the antigen. Without being bound by theory, it is hypothesized thatthe comprehensive complement is attributable to the antigen enrichmentstep that is performed prior to initial B cell recovery. Moreover, thisadvantage allows for the isolation and selection of antibodies withdifferent properties as these properties may vary depending on theepitopic specificity of the particular antibody.

Second, it has been found that the B cell selection protocolreproducibly yields a clonal B cell culture containing a single B cell,or its progeny, secreting a single monoclonal antibody that generallybinds to the desired antigen with a relatively high binding affinity,i.e. picomolar or better antigen binding affinities. By contrast, priorantibody selection methods tend to yield relatively few high affinityantibodies and therefore require extensive screening procedures toisolate an antibody with therapeutic potential. Without being bound bytheory, it is hypothesized that the protocol results in both in vivo Bcell immunization of the host (primary immunization) followed by asecond in vitro B cell stimulation (secondary antigen priming step) thatmay enhance the ability and propensity of the recovered clonal B cellsto secrete a single high affinity monoclonal antibody specific to theantigen target.

Third, it has been observed (as shown herein with IL-6 specific B cells)that the B cell selection protocol reproducibly yields enriched B cellsproducing IgG's that are, on average, highly selective (antigenspecific) to the desired target. Antigen-enriched B cells recovered bythese methods are believed to contain B cells capable of yielding thedesired full complement of epitopic specificities as discussed above.

Fourth, it has been observed that the B cell selection protocols, evenwhen used with small antigens, i.e., peptides of 100 amino acids orless, e.g., 5-50 amino acids long, reproducibly give rise to a clonal Bcell culture that secretes a single high affinity antibody to the smallantigen, e.g., a peptide. This is highly surprising as it is generallyquite difficult, labor intensive, and sometimes not even feasible toproduce high affinity antibodies to small peptides. Accordingly, theinvention can be used to produce therapeutic antibodies to desiredpeptide targets, e.g., viral, bacterial or autoantigen peptides, therebyallowing for the production of monoclonal antibodies with very discretebinding properties or even the production of a cocktail of monoclonalantibodies to different peptide targets, e.g., different viral strains.This advantage may especially be useful in the context of the productionof a therapeutic or prophylactic vaccine having a desired valency, suchas an HPV vaccine that induces protective immunity to different HPVstrains.

Fifth, the B cell selection protocol, particularly when used with Bcells derived from rabbits, tends to reproducibly yield antigen-specificantibody sequences that are very similar to endogenous humanimmunoglobulins (around 90% similar at the amino acid level) and thatcontain CDRs that possess a length very analogous to humanimmunoglobulins and therefore require little or no sequence modification(typically at most only a few CDR residues may be modified in the parentantibody sequence and no framework exogenous residues introduced) inorder to eliminate potential immunogenicity concerns. In particular,preferably the recombinant antibody will contain only the host (rabbit)CDR1 and CDR2 residues required for antigen recognition and the entireCDR3. Thereby, the high antigen binding affinity of the recoveredantibody sequences produced according to the B cell and antibodyselection protocol remains intact or substantially intact even withhumanization.

In sum, these method can be used to produce antibodies exhibiting higherbinding affinities to more distinct epitopes by the use of a moreefficient protocol than was previously known.

In a specific embodiment, the present invention provides a method foridentifying a single B cell that secretes an antibody specific to adesired antigen and that optionally possesses at least one desiredfunctional property such as affinity, avidity, cytolytic activity, andthe like by a process including the following steps:

a. immunizing a host against an antigen;

b. harvesting B cells from the host;

c. enriching the harvested B cells to increase the frequency ofantigen-specific cells;

d. creating at least one single cell suspension;

e. culturing a sub-population from the single cell suspension underconditions that favor the survival of a single antigen-specific B cellper culture well;

f. isolating B cells from the sub-population; and

g. determining whether the single B cell produces an antibody specificto the antigen.

Typically, these methods will further comprise an additional step ofisolating and sequencing, in whole or in part, the polypeptide andnucleic acid sequences encoding the desired antibody. These sequences ormodified versions or portions thereof can be expressed in desired hostcells in order to produce recombinant antibodies to a desired antigen.

As noted previously, it is believed that the clonal population of Bcells predominantly comprises antibody-secreting B cells producingantibody against the desired antigen. It is also believed based onexperimental results obtained with several antigens and with different Bcell populations that the clonally produced B cells and the isolatedantigen-specific B cells derived therefrom produced according to theinvention secrete a monoclonal antibody that is typically of relativelyhigh affinity and moreover is capable of efficiently and reproduciblyproducing a selection of monoclonal antibodies of greater epitopicvariability as compared to other methods of deriving monoclonalantibodies from cultured antigen-specific B cells. In an exemplaryembodiment the population of immune cells used in such B cell selectionmethods will be derived from a rabbit. However, other hosts that produceantibodies, including non-human and human hosts, can alternatively beused as a source of immune B cells. It is believed that the use ofrabbits as a source of B cells may enhance the diversity of monoclonalantibodies that may be derived by the methods. Also, the antibodysequences derived from rabbits according to the invention typicallypossess sequences having a high degree of sequence identity to humanantibody sequences making them favored for use in humans since theyshould possess little antigenicity. In the course of humanization, thefinal humanized antibody contains a much lower foreign/host residuecontent, usually restricted to a subset of the host CDR residues thatdiffer dramatically due to their nature versus the human target sequenceused in the grafting. This enhances the probability of complete activityrecovery in the humanized antibody protein.

The methods of antibody selection using an enrichment step disclosedherein include a step of obtaining a immune cell-containing cellpopulation from an immunized host. Methods of obtaining an immunecell-containing cell population from an immunized host are known in theart and generally include inducing an immune response in a host andharvesting cells from the host to obtain one or more cell populations.The response can be elicited by immunizing the host against a desiredantigen. Alternatively, the host used as a source of such immune cellscan be naturally exposed to the desired antigen such as an individualwho has been infected with a particular pathogen such as a bacterium orvirus or alternatively has mounted a specific antibody response to acancer that the individual is afflicted with.

Host animals are well-known in the art and include, but are not limitedto, guinea pig, rabbit, mouse, rat, non-human primate, human, as well asother mammals and rodents, chicken, cow, pig, goat, and sheep.Preferably the host is a mammal, more preferably, rabbit, mouse, rat, orhuman. When exposed to an antigen, the host produces antibodies as partof the native immune response to the antigen. As mentioned, the immuneresponse can occur naturally, as a result of disease, or it can beinduced by immunization with the antigen. Immunization can be performedby any method known in the art, such as, by one or more injections ofthe antigen with or without an agent to enhance immune response, such ascomplete or incomplete Freund's adjuvant. In another embodiment, theinvention also contemplates intrasplenic immunization. As an alternativeto immunizing a host animal in vivo, the method can comprise immunizinga host cell culture in vitro.

After allowing time for the immune response (e.g., as measured by serumantibody detection), host animal cells are harvested to obtain one ormore cell populations. In a preferred embodiment, a harvested cellpopulation is screened for antibody binding strength and/or antibodyfunctionality. A harvested cell population is preferably from at leastone of the spleen, lymph nodes, bone marrow, and/or peripheral bloodmononuclear cells (PBMCs). The cells can be harvested from more than onesource and pooled. Certain sources may be preferred for certainantigens. For example, the spleen, lymph nodes, and PBMCs are preferredfor IL-6; and the lymph nodes are preferred for TNF. The cell populationis harvested about 20 to about 90 days or increments therein afterimmunization, preferably about 50 to about 60 days. A harvested cellpopulation and/or a single cell suspension therefrom can be enriched,screened, and/or cultured for antibody selection. The frequency ofantigen-specific cells within a harvested cell population is usuallyabout 1% to about 5%, or increments therein.

In one embodiment, a single cell suspension from a harvested cellpopulation is enriched, preferably by using Miltenyi beads. From theharvested cell population having a frequency of antigen-specific cellsof about 1% to about 5%, an enriched cell population is thus derivedhaving a frequency of antigen-specific cells approaching 100%.

The method of antibody selection using an enrichment step includes astep of producing antibodies from at least one antigen-specific cellfrom an enriched cell population. Methods of producing antibodies invitro are well known in the art, and any suitable method can beemployed. In one embodiment, an enriched cell population, such as anantigen-specific single cell suspension from a harvested cellpopulation, is plated at various cell densities, such as 50, 100, 250,500, or other increments between 1 and 1000 cells per well. Preferably,the sub-population comprises no more than about 10,000 antigen-specific,antibody-secreting cells, more preferably about 50-10,000, about50-5,000, about 50-1,000, about 50-500, about 50-250 antigen-specific,antibody-secreting cells, or increments therein. Then, thesesub-populations are cultured with suitable medium (e.g., an activated Tcell conditioned medium, particularly 1-5% activated rabbit T cellconditioned medium) on a feeder layer, preferably under conditions thatfavor the survival of a single proliferating antibody-secreting cell perculture well. The feeder layer, generally comprised of irradiated cellmatter, e.g., EL4B cells, does not constitute part of the cellpopulation. The cells are cultured in a suitable media for a timesufficient for antibody production, for example about 1 day to about 2weeks, about 1 day to about 10 days, at least about 3 days, about 3 toabout 5 days, about 5 days to about 7 days, at least about 7 days, orother increments therein. In one embodiment, more than onesub-population is cultured simultaneously. Preferably, a singleantibody-producing cell and progeny thereof survives in each well,thereby providing a clonal population of antigen-specific B cells ineach well. At this stage, the immunoglobulin G (IgG) produced by theclonal population is highly correlative with antigen specificity. In apreferred embodiment, the IgGs exhibit a correlation with antigenspecificity that is greater than about 50%, more preferably greater than70%, 85%, 90%, 95%, 99%, or increments therein. See FIG. 3, whichdemonstrates an exemplary correlation for IL-6. The correlations weredemonstrated by setting up B cell cultures under limiting conditions toestablish single antigen-specific antibody products per well.Antigen-specific versus general IgG synthesis was compared. Threepopulations were observed: IgG that recognized a single format ofantigen (biotinylated and direct coating), detectable IgG and antigenrecognition irrespective of immobilization, and IgG production alone.IgG production was highly correlated with antigen-specificity.

A supernatant containing the antibodies is optionally collected, whichcan be can be enriched, screened, and/or cultured for antibody selectionaccording to the steps described above. In one embodiment, thesupernatant is enriched (preferably by an antigen-specificity assay,especially an ELISA assay) and/or screened for antibody functionality.

In another embodiment, the enriched, preferably clonal, antigen-specificB cell population from which a supernatant described above is optionallyscreened in order to detect the presence of the desired secretedmonoclonal antibody is used for the isolation of a few B cells,preferably a single B cell, which is then tested in an appropriate assayin order to confirm the presence of a single antibody-producing B cellin the clonal B cell population. In one embodiment about 1 to about 20cells are isolated from the clonal B cell population, preferably lessthan about 15, 12, 10, 5, or 3 cells, or increments therein, mostpreferably a single cell. The screen is preferably effected by anantigen-specificity assay, especially a halo assay. The halo assay canbe performed with the full length protein, or a fragment thereof. Theantibody-containing supernatant can also be screened for at least oneof: antigen binding affinity; agonism or antagonism of antigen-ligandbinding, induction or inhibition of the proliferation of a specifictarget cell type; induction or inhibition of lysis of a target cell, andinduction or inhibition of a biological pathway involving the antigen.

The identified antigen-specific cell can be used to derive thecorresponding nucleic acid sequences encoding the desired monoclonalantibody. (An AluI digest can confirm that only a single monoclonalantibody type is produced per well.) As mentioned above, these sequencescan be mutated, such as by humanization, in order to render themsuitable for use in human medicaments.

As mentioned, the enriched B cell population used in the process canalso be further enriched, screened, and/or cultured for antibodyselection according to the steps described above which can be repeatedor performed in a different order. In a preferred embodiment, at leastone cell of an enriched, preferably clonal, antigen-specific cellpopulation is isolated, cultured, and used for antibody selection.

Thus, in one embodiment, the present invention provides a methodcomprising:

a. harvesting a cell population from an immunized host to obtain aharvested cell population;

b. creating at least one single cell suspension from a harvested cellpopulation;

c. enriching at least one single cell suspension, preferably bychromatography, to form a first enriched cell population;

d. enriching the first enriched cell population, preferably by ELISAassay, to form a second enriched cell population which preferably isclonal, i.e., it contains only a single type of antigen-specific B cell;

e. enriching the second enriched cell population, preferably by haloassay, to form a third enriched cell population containing a single or afew number of B cells that produce an antibody specific to a desiredantigen; and

f. selecting an antibody produced by an antigen-specific cell isolatedfrom the third enriched cell population.

The method can further include one or more steps of screening theharvested cell population for antibody binding strength (affinity,avidity) and/or antibody functionality. Suitable screening stepsinclude, but are not limited to, assay methods that detect: whether theantibody produced by the identified antigen-specific B cell produces anantibody possessing a minimal antigen binding affinity, whether theantibody agonizes or antagonizes the binding of a desired antigen to aligand; whether the antibody induces or inhibits the proliferation of aspecific cell type; whether the antibody induces or elicits a cytolyticreaction against target cells; whether the antibody binds to a specificepitope; and whether the antibody modulates (inhibits or agonizes) aspecific biological pathway or pathways involving the antigen.

Similarly, the method can include one or more steps of screening thesecond enriched cell population for antibody binding strength and/orantibody functionality.

The method can further include a step of sequencing the polypeptidesequence or the corresponding nucleic acid sequence of the selectedantibody. The method can also include a step of producing a recombinantantibody using the sequence, a fragment thereof, or a geneticallymodified version of the selected antibody. Methods for mutating antibodysequences in order to retain desired properties are well known to thoseskilled in the art and include humanization, chimerisation, productionof single chain antibodies; these mutation methods can yield recombinantantibodies possessing desired effector function, immunogenicity,stability, removal or addition of glycosylation, and the like. Therecombinant antibody can be produced by any suitable recombinant cell,including, but not limited to mammalian cells such as CHO, COS, BHK,HEK-293, bacterial cells, yeast cells, plant cells, insect cells, andamphibian cells. In one embodiment, the antibodies are expressed inpolyploidal yeast cells, i.e., diploid yeast cells, particularly Pichia.

In one embodiment, the method comprises:

a. immunizing a host against an antigen to yield host antibodies;

b. screening the host antibodies for antigen specificity andneutralization;

c. harvesting B cells from the host;

d. enriching the harvested B cells to create an enriched cell populationhaving an increased frequency of antigen-specific cells;

e. culturing one or more sub-populations from the enriched cellpopulation under conditions that favor the survival of a single B cellto produce a clonal population in at least one culture well;

f. determining whether the clonal population produces an antibodyspecific to the antigen;

g. isolating a single B cell; and

h. sequencing the nucleic acid sequence of the antibody produced by thesingle B cell.

Methods of Humanizing Antibodies

In another embodiment of the invention, there is provided a method forhumanizing antibody heavy and light chains. In this embodiment, thefollowing method is followed for the humanization of the heavy and lightchains:

Light Chain

1. Identify the amino acid that is the first one following the signalpeptide sequence. This is the start of Framework 1. The signal peptidestarts at the first initiation methionine and is typically, but notnecessarily 22 amino acids in length for rabbit light chain proteinsequences. The start of the mature polypeptide can also be determinedexperimentally by N-terminal protein sequencing, or can be predictedusing a prediction algorithm. This is also the start of Framework 1 asclassically defined by those in the field.

Example: RbtVL Amino acid residue 2 in FIG. 2, starting ‘AYDM . . . ’

2. Identify the end of Framework 3. This is typically 86-90 amino acidsfollowing the start of Framework 1 and is typically a cysteine residuepreceded by two tyrosine residues. This is the end of the Framework 3 asclassically defined by those in the field.

Example: RbtVL amino acid residue 88 in FIG. 2, ending as ‘TYYC’

3. Use the rabbit light chain sequence of the polypeptide starting fromthe beginning of Framework 1 to the end of Framework 3 as defined aboveand perform a sequence homology search for the most similar humanantibody protein sequences. This will typically be a search againsthuman germline sequences prior to antibody maturation in order to reducethe possibility of immunogenicity, however any human sequences can beused. Typically a program like BLAST can be used to search a database ofsequences for the most homologous. Databases of human antibody sequencescan be found from various sources such as NCBI (National Center forBiotechnology Information).

Example: RbtVL amino acid sequence from residues numbered 1 through 88in FIG. 2 is BLASTed against a human antibody germline database. The topthree unique returned sequences are shown in FIG. 2 as L12A, V1 andVx02.

4. Generally the most homologous human germline variable light chainsequence is then used as the basis for humanization. However thoseskilled in the art may decide to use another sequence that wasn't thehighest homology as determined by the homology algorithm, based on otherfactors including sequence gaps and framework similarities.

Example: In FIG. 2, L12A was the most homologous human germline variablelight chain sequence and is used as the basis for the humanization ofRbtVL.

5. Determine the framework and CDR arrangement (FR1, FR2, FR3, CDR1 &CDR2) for the human homolog being used for the light chain humanization.This is using the traditional layout as described in the field. Alignthe rabbit variable light chain sequence with the human homolog, whilemaintaining the layout of the framework and CDR regions.

Example: In FIG. 2, the RbtVL sequence is aligned with the humanhomologous sequence L12A, and the framework and CDR domains areindicated.

6. Replace the human homologous light chain sequence CDR1 and CDR2regions with the CDR1 and CDR2 sequences from the rabbit sequence. Ifthere are differences in length between the rabbit and human CDRsequences then use the entire rabbit CDR sequences and their lengths. Itis possible that the specificity, affinity and/or immunogenicity of theresulting humanized antibody may be unaltered if smaller or largersequence exchanges are performed, or if specific residue(s) are altered,however the exchanges as described have been used successfully, but donot exclude the possibility that other changes may be permitted.

Example: In FIG. 2, the CDR1 and CDR2 amino acid residues of the humanhomologous variable light chain L12A are replaced with the CDR1 and CDR2amino acid sequences from the RbtVL rabbit antibody light chainsequence. The human L12A frameworks 1, 2 and 3 are unaltered. Theresulting humanized sequence is shown below as VLh from residuesnumbered 1 through 88. Note that the only residues that are differentfrom the L12A human sequence are underlined, and are thus rabbit-derivedamino acid residues. In this example only 8 of the 88 residues aredifferent than the human sequence.

7. After framework 3 of the new hybrid sequence created in Step 6,attach the entire CDR3 of the rabbit light chain antibody sequence. TheCDR3 sequence can be of various lengths, but is typically 9 to 15 aminoacid residues in length. The CDR3 region and the beginning of thefollowing framework 4 region are defined classically and identifiable bythose skilled in the art. Typically the beginning of Framework 4, andthus after the end of CDR3 consists of the sequence ‘FGGG . . . ’,however some variation may exist in these residues.

Example: In FIG. 2, the CDR3 of RbtVL (amino acid residues numbered89-100) is added after the end of framework 3 in the humanized sequenceindicated as VLh.

8. The rabbit light chain framework 4, which is typically the final 11amino acid residues of the variable light chain and begins as indicatedin Step 7 above and typically ends with the amino acid sequence ‘ . . .VVKR’ is replaced with the nearest human light chain framework 4homolog, usually from germline sequence. Frequently this human lightchain framework 4 is of the sequence ‘FGGGTKVEIKR’. It is possible thatother human light chain framework 4 sequences that are not the mosthomologous or otherwise different may be used without affecting thespecificity, affinity and/or immunogenicity of the resulting humanizedantibody. This human light chain framework 4 sequence is added to theend of the variable light chain humanized sequence immediately followingthe CDR3 sequence from Step 7 above. This is now the end of the variablelight chain humanized amino acid sequence.

Example: In FIG. 2, Framework 4 (FR4) of the RbtVL rabbit light chainsequence is shown above a homologous human FR4 sequence. The human FR4sequence is added to the humanized variable light chain sequence (VLh)right after the end of the CD3 region added in Step 7 above.

Heavy Chain

1. Identify the amino acid that is the first one following the signalpeptide sequence. This is the start of Framework 1. The signal peptidestarts at the first initiation methionine and is typically 19 aminoacids in length for rabbit heavy chain protein sequences. Typically, butnot necessarily always, the final 3 amino acid residues of a rabbitheavy chain signal peptide are ‘ . . . VQC’, followed by the start ofFramework 1. The start of the mature polypeptide can also be determinedexperimentally by N-terminal protein sequencing, or can be predictedusing a prediction algorithm. This is also the start of Framework 1 asclassically defined by those in the field.

Example: RbtVH Amino acid residue 1 in FIG. 2, starting ‘QEQL . . . ’

2. Identify the end of Framework 3. This is typically 95-100 amino acidsfollowing the start of Framework 1 and typically has the final sequenceof ‘ . . . CAR’ (although the alanine can also be a valine). This is theend of the Framework 3 as classically defined by those in the field.

Example: RbtVH amino acid residue 98 in FIG. 2, ending as ‘ . . . FCVR’.

3. Use the rabbit heavy chain sequence of the polypeptide starting fromthe beginning of Framework 1 to the end of Framework 3 as defined aboveand perform a sequence homology search for the most similar humanantibody protein sequences. This will typically be against a database ofhuman germline sequences prior to antibody maturation in order to reducethe possibility of immunogenicity, however any human sequences can beused. Typically a program like BLAST can be used to search a database ofsequences for the most homologous. Databases of human antibody sequencescan be found from various sources such as NCBI (National Center forBiotechnology Information).

Example: RbtVH amino acid sequence from residues numbered 1 through 98in FIG. 2 is BLASTed against a human antibody germline database. The topthree unique returned sequences are shown in FIGS. 2 as 3-64-04,3-66-04, and 3-53-02.

4. Generally the most homologous human germline variable heavy chainsequence is then used as the basis for humanization. However thoseskilled in the art may decide to use another sequence that wasn't themost homologous as determined by the homology algorithm, based on otherfactors including sequence gaps and framework similarities.

Example: 3-64-04 in FIG. 2 was the most homologous human germlinevariable heavy chain sequence and is used as the basis for thehumanization of RbtVH.

5. Determine the framework and CDR arrangement (FR1, FR2, FR3, CDR1 &CDR2) for the human homolog being used for the heavy chain humanization.This is using the traditional layout as described in the field. Alignthe rabbit variable heavy chain sequence with the human homolog, whilemaintaining the layout of the framework and CDR regions.

Example: In FIG. 2, the RbtVH sequence is aligned with the humanhomologous sequence 3-64-04, and the framework and CDR domains areindicated.

6. Replace the human homologous heavy chain sequence CDR1 and CDR2regions with the CDR1 and CDR2 sequences from the rabbit sequence. Ifthere are differences in length between the rabbit and human CDRsequences then use the entire rabbit CDR sequences and their lengths. Inaddition, it may be necessary to replace the final three amino acids ofthe human heavy chain Framework 1 region with the final three aminoacids of the rabbit heavy chain Framework 1. Typically but not always,in rabbit heavy chain Framework 1 these three residues follow a Glycineresidue preceded by a Serine residue. In addition, it may be necessaryreplace the final amino acid of the human heavy chain Framework 2 regionwith the final amino acid of the rabbit heavy chain Framework 2.Typically, but not necessarily always, this is a Glycine residuepreceded by an Isoleucine residue in the rabbit heavy chain Framework 2.It is possible that the specificity, affinity and/or immunogenicity ofthe resulting humanized antibody may be unaltered if smaller or largersequence exchanges are performed, or if specific residue(s) are altered,however the exchanges as described have been used successfully, but donot exclude the possibility that other changes may be permitted. Forexample, a tryptophan amino acid residue typically occurs four residuesprior to the end of the rabbit heavy chain CDR2 region, whereas in humanheavy chain CDR2 this residue is typically a Serine residue. Changingthis rabbit tryptophan residue to a the human Serine residue at thisposition has been demonstrated to have minimal to no effect on thehumanized antibody's specificity or affinity, and thus further minimizesthe content of rabbit sequence-derived amino acid residues in thehumanized sequence.

Example: In FIG. 2, The CDR1 and CDR2 amino acid residues of the humanhomologous variable heavy chain are replaced with the CDR1 and CDR2amino acid sequences from the RbtVH rabbit antibody light chainsequence, except for the boxed residue, which is tryptophan in therabbit sequence (position number 63) and Serine at the same position inthe human sequence, and is kept as the human Serine residue. In additionto the CDR1 and CDR2 changes, the final three amino acids of Framework 1(positions 28-30) as well as the final residue of Framework 2 (position49) are retained as rabbit amino acid residues instead of human. Theresulting humanized sequence is shown below as VHh from residuesnumbered 1 through 98. Note that the only residues that are differentfrom the 3-64-04 human sequence are underlined, and are thusrabbit-derived amino acid residues. In this example only 15 of the 98residues are different than the human sequence.

7. After framework 3 of the new hybrid sequence created in Step 6,attach the entire CDR3 of the rabbit heavy chain antibody sequence. TheCDR3 sequence can be of various lengths, but is typically 5 to 19 aminoacid residues in length. The CDR3 region and the beginning of thefollowing framework 4 region are defined classically and areidentifiable by those skilled in the art. Typically the beginning offramework 4, and thus after the end of CDR3 consists of the sequenceWGXG . . . (where X is usually Q or P), however some variation may existin these residues.

Example: The CDR3 of RbtVH (amino acid residues numbered 99-110) isadded after the end of framework 3 in the humanized sequence indicatedas VHh.

8. The rabbit heavy chain framework 4, which is typically the final 11amino acid residues of the variable heavy chain and begins as indicatedin Step 7 above and typically ends with the amino acid sequence ‘ . . .TVSS’ is replaced with the nearest human heavy chain framework 4homolog, usually from germline sequence. Frequently this human heavychain framework 4 is of the sequence ‘WGQGTLVTVSS’. It is possible thatother human heavy chain framework 4 sequences that are not the mosthomologous or otherwise different may be used without affecting thespecificity, affinity and/or immunogenicity of the resulting humanizedantibody. This human heavy chain framework 4 sequence is added to theend of the variable heavy chain humanized sequence immediately followingthe CDR3 sequence from Step 7 above. This is now the end of the variableheavy chain humanized amino acid sequence.

Example: In FIG. 2, framework 4 (FR4) of the RbtVH rabbit heavy chainsequence is shown above a homologous human heavy FR4 sequence. The humanFR4 sequence is added to the humanized variable heavy chain sequence(VHh) right after the end of the CD3 region added in Step 7 above.

In addition, FIG. 15 depicts preferred humanized anti-IL-6 variableheavy and variable light chain sequences humanized from the variableheavy and light regions in Ab1 according to the invention. Thesehumanized light and heavy chain regions are respectively contained inthe polypeptides contained in SEQ ID NO:647, 648, 649, 650, 651, or 709,and in SEQ ID NO:652, 653, 654, 655, 656, 657 or 658. The CDR2 of thehumanized variable heavy region in SEQ ID NO:657 (containing a serinesubstitution in CDR2) is contained in SEQ ID NO:659.

Methods of Producing Antibodies and Fragments Thereof

The invention is also directed to the production of the antibodiesdescribed herein or fragments thereof. Recombinant polypeptidescorresponding to the antibodies described herein or fragments thereofare secreted from polyploidal, preferably diploid or tetraploid strainsof mating competent yeast. In an exemplary embodiment, the invention isdirected to methods for producing these recombinant polypeptides insecreted form for prolonged periods using cultures comprising polyploidyeast, i.e., at least several days to a week, more preferably at least amonth or several months, and even more preferably at least 6 months to ayear or longer. These polyploid yeast cultures will express at least10-25 mg/liter of the polypeptide, more preferably at least 50-250mg/liter, still more preferably at least 500-1000 mg/liter, and mostpreferably a gram per liter or more of the recombinant polypeptide(s).

In one embodiment of the invention a pair of genetically marked yeasthaploid cells are transformed with expression vectors comprisingsubunits of a desired heteromultimeric protein. One haploid cellcomprises a first expression vector, and a second haploid cell comprisesa second expression vector. In another embodiment diploid yeast cellswill be transformed with one or more expression vectors that provide forthe expression and secretion of one or more of the recombinantpolypeptides. In still another embodiment a single haploid cell may betransformed with one or more vectors and used to produce a polyploidalyeast by fusion or mating strategies. In yet another embodiment adiploid yeast culture may be transformed with one or more vectorsproviding for the expression and secretion of a desired polypeptide orpolypeptides. These vectors may comprise vectors e.g., linearizedplasmids or other linear DNA products that integrate into the yeastcell's genome randomly, through homologous recombination, or using arecombinase such as Cre/Lox or Flp/Frt. Optionally, additionalexpression vectors may be introduced into the haploid or diploid cells;or the first or second expression vectors may comprise additional codingsequences; for the synthesis of heterotrimers; heterotetramers; etc. Theexpression levels of the non-identical polypeptides may be individuallycalibrated, and adjusted through appropriate selection, vector copynumber, promoter strength and/or induction and the like. The transformedhaploid cells are genetically crossed or fused. The resulting diploid ortetraploid strains are utilized to produce and secrete fully assembledand biologically functional proteins, humanized antibodies describedherein or fragments thereof.

The use of diploid or tetraploid cells for protein production providesfor unexpected benefits. The cells can be grown for production purposes,i.e. scaled up, and for extended periods of time, in conditions that canbe deleterious to the growth of haploid cells, which conditions mayinclude high cell density; growth in minimal media; growth at lowtemperatures; stable growth in the absence of selective pressure; andwhich may provide for maintenance of heterologous gene sequenceintegrity and maintenance of high level expression over time. Withoutwishing to be bound thereby, the inventors theorize that these benefitsmay arise, at least in part, from the creation of diploid strains fromtwo distinct parental haploid strains. Such haploid strains can comprisenumerous minor autotrophic mutations, which mutations are complementedin the diploid or tetraploid, enabling growth and enhanced productionunder highly selective conditions.

Transformed mating competent haploid yeast cells provide a geneticmethod that enables subunit pairing of a desired protein. Haploid yeaststrains are transformed with each of two expression vectors, a firstvector to direct the synthesis of one polypeptide chain and a secondvector to direct the synthesis of a second, non-identical polypeptidechain. The two haploid strains are mated to provide a diploid host whereoptimized target protein production can be obtained.

Optionally, additional non-identical coding sequence(s) are provided.Such sequences may be present on additional expression vectors or in thefirst or the second expression vectors. As is known in the art, multiplecoding sequences may be independently expressed from individualpromoters; or may be coordinately expressed through the inclusion of an“internal ribosome entry site” or “IRES”, which is an element thatpromotes direct internal ribosome entry to the initiation codon, such asATG, of a cistron (a protein encoding region), thereby leading to thecap-independent translation of the gene. IRES elements functional inyeast are described by Thompson et al. (2001) P.N.A.S. 98:12866-12868.

In one embodiment of the invention, antibody sequences are produced incombination with a secretory J chain, which provides for enhancedstability of IgA (see U.S. Pat. Nos. 5,959,177; and 5,202,422).

In a preferred embodiment the two haploid yeast strains are eachauxotrophic, and require supplementation of media for growth of thehaploid cells. The pair of auxotrophs are complementary, such that thediploid product will grow in the absence of the supplements required forthe haploid cells. Many such genetic markers are known in yeast,including requirements for amino acids (e.g. met, lys, his, arg, etc.),nucleosides (e.g. ura3, ade1, etc.); and the like. Amino acid markersmay be preferred for the methods of the invention. Alternatively diploidcells which contain the desired vectors can be selected by other means,e.g., by use of other markers, such as green fluorescent protein,antibiotic resistance genes, various dominant selectable markers, andthe like.

Two transformed haploid cells may be genetically crossed and diploidstrains arising from this mating event selected by their hybridnutritional requirements and/or antibiotic resistance spectra.Alternatively, populations of the two transformed haploid strains arespheroplasted and fused, and diploid progeny regenerated and selected.By either method, diploid strains can be identified and selectivelygrown based on their ability to grow in different media than theirparents. For example, the diploid cells may be grown in minimal mediumthat may include antibiotics. The diploid synthesis strategy has certainadvantages. Diploid strains have the potential to produce enhancedlevels of heterologous protein through broader complementation tounderlying mutations, which may impact the production and/or secretionof recombinant protein. Furthermore, once stable strains have beenobtained, any antibiotics used to select those strains do notnecessarily need to be continuously present in the growth media.

As noted above, in some embodiments a haploid yeast may be transformedwith a single or multiple vectors and mated or fused with anon-transformed cell to produce a diploid cell containing the vector orvectors. In other embodiments, a diploid yeast cell may be transformedwith one or more vectors that provide for the expression and secretionof a desired heterologous polypeptide by the diploid yeast cell.

In one embodiment of the invention, two haploid strains are transformedwith a library of polypeptides, e.g. a library of antibody heavy orlight chains. Transformed haploid cells that synthesize the polypeptidesare mated with the complementary haploid cells. The resulting diploidcells are screened for functional protein. The diploid cells provide ameans of rapidly, conveniently and inexpensively bringing together alarge number of combinations of polypeptides for functional testing.This technology is especially applicable for the generation ofheterodimeric protein products, where optimized subunit synthesis levelsare critical for functional protein expression and secretion.

In another embodiment of the invention, the expression level ratio ofthe two subunits is regulated in order to maximize product generation.Heterodimer subunit protein levels have been shown previously to impactthe final product generation (Simmons L C, J Immunol Methods. 2002 May1; 263(1-2):133-47). Regulation can be achieved prior to the mating stepby selection for a marker present on the expression vector. By stablyincreasing the copy number of the vector, the expression level can beincreased. In some cases, it may be desirable to increase the level ofone chain relative to the other, so as to reach a balanced proportionbetween the subunits of the polypeptide. Antibiotic resistance markersare useful for this purpose, e.g. Zeocin resistance marker, G418resistance, etc. and provide a means of enrichment for strains thatcontain multiple integrated copies of an expression vector in a strainby selecting for transformants that are resistant to higher levels ofZeocin or G418. The proper ratio, e.g. 1:1; 1:2; etc. of the subunitgenes may be important for efficient protein production. Even when thesame promoter is used to transcribe both subunits, many other factorscontribute to the final level of protein expressed and therefore, it canbe useful to increase the number of copies of one encoded gene relativeto the other. Alternatively, diploid strains that produce higher levelsof a polypeptide, relative to single copy vector strains, are created bymating two haploid strains, both of which have multiple copies of theexpression vectors.

Host cells are transformed with the above-described expression vectors,mated to form diploid strains, and cultured in conventional nutrientmedia modified as appropriate for inducing promoters, selectingtransformants or amplifying the genes encoding the desired sequences. Anumber of minimal media suitable for the growth of yeast are known inthe art. Any of these media may be supplemented as necessary with salts(such as sodium chloride, calcium, magnesium, and phosphate), buffers(such as phosphate, HEPES), nucleosides (such as adenosine andthymidine), antibiotics, trace elements, and glucose or an equivalentenergy source. Any other necessary supplements may also be included atappropriate concentrations that would be known to those skilled in theart. The culture conditions, such as temperature, pH and the like, arethose previously used with the host cell selected for expression, andwill be apparent to the ordinarily skilled artisan.

Secreted proteins are recovered from the culture medium. A proteaseinhibitor, such as phenyl methyl sulfonyl fluoride (PMSF) may be usefulto inhibit proteolytic degradation during purification, and antibioticsmay be included to prevent the growth of adventitious contaminants. Thecomposition may be concentrated, filtered, dialyzed, etc., using methodsknown in the art.

The diploid cells of the invention are grown for production purposes.Such production purposes desirably include growth in minimal media,which media lacks pre-formed amino acids and other complex biomolecules,e.g., media comprising ammonia as a nitrogen source, and glucose as anenergy and carbon source, and salts as a source of phosphate, calciumand the like. Preferably such production media lacks selective agentssuch as antibiotics, amino acids, purines, pyrimidines, etc. The diploidcells can be grown to high cell density, for example at least about 50g/L; more usually at least about 100 g/L; and may be at least about 300,about 400, about 500 g/L or more.

In one embodiment of the invention, the growth of the subject cells forproduction purposes is performed at low temperatures, which temperaturesmay be lowered during log phase, during stationary phase, or both. Theterm “low temperature” refers to temperatures of at least about 15° C.,more usually at least about 17° C., and may be about 20° C., and isusually not more than about 25° C., more usually not more than about 22°C. In another embodiment of the invention, the low temperature isusually not more than about 28° C. Growth temperature can impact theproduction of full-length secreted proteins in production cultures, anddecreasing the culture growth temperature can strongly enhance theintact product yield. The decreased temperature appears to assistintracellular trafficking through the folding and post-translationalprocessing pathways used by the host to generate the target product,along with reduction of cellular protease degradation.

The methods of the invention provide for expression of secreted, activeprotein, preferably a mammalian protein. In one embodiment, secreted,“active antibodies”, as used herein, refers to a correctly foldedmultimer of at least two properly paired chains, which accurately bindsto its cognate antigen. Expression levels of active protein are usuallyat least about 10-50 mg/liter culture, more usually at least about 100mg/liter, preferably at least about 500 mg/liter, and may be 1000mg/liter or more.

The methods of the invention can provide for increased stability of thehost and heterologous coding sequences during production. The stabilityis evidenced, for example, by maintenance of high levels of expressionof time, where the starting level of expression is decreased by not morethan about 20%, usually not more than 10%, and may be decreased by notmore than about 5% over about 20 doublings, 50 doublings, 100 doublings,or more.

The strain stability also provides for maintenance of heterologous genesequence integrity over time, where the sequence of the active codingsequence and requisite transcriptional regulatory elements aremaintained in at least about 99% of the diploid cells, usually in atleast about 99.9% of the diploid cells, and preferably in at least about99.99% of the diploid cells over about 20 doublings, 50 doublings, 100doublings, or more. Preferably, substantially all of the diploid cellsmaintain the sequence of the active coding sequence and requisitetranscriptional regulatory elements.

Other methods of producing antibodies are well known to those ofordinary skill in the art. For example, methods of producing chimericantibodies are now well known in the art (See, for example, U.S. Pat.No. 4,816,567 to Cabilly et al.; Morrison et al., P.N.A.S. USA,81:8651-55 (1984); Neuberger, M. S. et al., Nature, 314:268-270 (1985);Boulianne, G. L. et al., Nature, 312:643-46 (1984), the disclosures ofeach of which are herein incorporated by reference in their entireties).

Likewise, other methods of producing humanized antibodies are now wellknown in the art (See, for example, U.S. Pat. Nos. 5,530,101, 5,585,089,5,693,762, and 6,180,370 to Queen et al; U.S. Pat. Nos. 5,225,539 and6,548,640 to Winter; U.S. Pat. Nos. 6,054,297, 6,407,213 and 6,639,055to Carter et al; U.S. Pat. No. 6,632,927 to Adair; Jones, P. T. et al,Nature, 321:522-525 (1986); Reichmann, L., et al, Nature, 332:323-327(1988); Verhoeyen, M, et al, Science, 239:1534-36 (1988), thedisclosures of each of which are herein incorporated by reference intheir entireties).

Antibody polypeptides of the invention having IL-6 binding specificitymay also be produced by constructing, using conventional techniques wellknown to those of ordinary skill in the art, an expression vectorcontaining an operon and a DNA sequence encoding an antibody heavy chainin which the DNA sequence encoding the CDRs required for antibodyspecificity is derived from a non-human cell source, preferably a rabbitB-cell source, while the DNA sequence encoding the remaining parts ofthe antibody chain is derived from a human cell source.

A second expression vector is produced using the same conventional meanswell known to those of ordinary skill in the art, said expression vectorcontaining an operon and a DNA sequence encoding an antibody light chainin which the DNA sequence encoding the CDRs required for antibodyspecificity is derived from a non-human cell source, preferably a rabbitB-cell source, while the DNA sequence encoding the remaining parts ofthe antibody chain is derived from a human cell source.

The expression vectors are transfected into a host cell by conventiontechniques well known to those of ordinary skill in the art to produce atransfected host cell, said transfected host cell cultured byconventional techniques well known to those of ordinary skill in the artto produce said antibody polypeptides.

The host cell may be co-transfected with the two expression vectorsdescribed above, the first expression vector containing DNA encoding anoperon and a light chain-derived polypeptide and the second vectorcontaining DNA encoding an operon and a heavy chain-derived polypeptide.The two vectors contain different selectable markers, but preferablyachieve substantially equal expression of the heavy and light chainpolypeptides. Alternatively, a single vector may be used, the vectorincluding DNA encoding both the heavy and light chain polypeptides. Thecoding sequences for the heavy and light chains may comprise cDNA.

The host cells used to express the antibody polypeptides may be either abacterial cell such as E. coli, or a eukaryotic cell. In a particularlypreferred embodiment of the invention, a mammalian cell of awell-defined type for this purpose, such as a myeloma cell or a Chinesehamster ovary (CHO) cell line may be used.

The general methods by which the vectors may be constructed,transfection methods required to produce the host cell and culturingmethods required to produce the antibody polypeptides from said hostcells all include conventional techniques. Although preferably the cellline used to produce the antibody is a mammalian cell line, any othersuitable cell line, such as a bacterial cell line such as an E.coli-derived bacterial strain, or a yeast cell line, may alternativelybe used.

Similarly, once produced the antibody polypeptides may be purifiedaccording to standard procedures in the art, such as for examplecross-flow filtration, ammonium sulphate precipitation, affinity columnchromatography and the like.

The antibody polypeptides described herein may also be used for thedesign and synthesis of either peptide or non-peptide mimetics thatwould be useful for the same therapeutic applications as the antibodypolypeptides of the invention. See, for example, Saragobi et al,Science, 253:792-795 (1991), the contents of which is hereinincorporated by reference in its entirety.

Exemplary Embodiments of Heavy and Light Chain Polypeptides andPolynucleotides

This section recites exemplary embodiments of heavy and light chainpolypeptides, as well as exemplary polynucleotides encoding suchpolypeptides. These exemplary polynucleotides are suitable forexpression in the disclosed Pichia expression system.

In certain embodiments, the present invention encompassespolynucleotides having at least 70%, such as at least 75%, at least 80%,at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to the polynucleotides recited in thisapplication or that encode polypeptides recited in this application, orthat hybridize to said polynucleotides under conditions oflow-stringency, moderate-stringency, or high-stringency conditions,preferably those that encode polypeptides (e.g. an immunoglobulin heavyand light chain, a single-chain antibody, an antibody fragment, etc.)that have at least one of the biological activities set forth herein,including without limitation thereto specific binding to an IL-6polypeptide. In another aspect, the invention encompasses a compositioncomprising such a polynucleotide and/or a polypeptide encoded by such apolynucleotide. In yet another aspect, the invention encompasses amethod of treatment of a disease or condition associated with IL-6 orthat may be prevented, treated, or ameliorated with an IL-6 antagonist(e.g. cachexia, cancer fatigue, arthritis, etc.) comprisingadministration of a composition comprising such a polynucleotide and/orpolypeptide.

In certain preferred embodiments, a heavy chain polypeptide willcomprise one or more of the CDR sequences of the heavy and/or lightchain polypeptides recited herein (including those contained in theheavy and light chain polypeptides recited herein) and one or more ofthe framework region polypeptides recited herein, including thosedepicted in FIG. 2, FIG. 15, FIG. 16, and contained in the heavy andlight chain polypeptide sequences recited herein. In certain preferredembodiments, a heavy chain polypeptide will comprise one or moreFramework 4 region sequences as depicted in FIG. 2, FIG. 15, FIG. 16, oras contained in a heavy or light chain polypeptide recited herein.

In certain preferred embodiments, a light chain polypeptide willcomprise one or more of the CDR sequences of the heavy and/or lightchain polypeptides recited herein (including those contained in theheavy and light chain polypeptides recited herein) and one or more ofthe Framework region polypeptides recited herein, including thosedepicted in FIG. 2, FIG. 15, FIG. 16, and contained in the heavy andlight chain polypeptide sequences recited herein. In certain preferredembodiments, a light chain polypeptide will comprise one or moreFramework 4 region sequences as depicted in FIG. 2, FIG. 15, FIG. 16, oras contained in a heavy or light chain polypeptide recited herein.

In any of the embodiments recited herein, certain of the sequencesrecited may be substituted for each other, unless the context indicatesotherwise. The recitation that particular sequences may be substitutedfor one another, where such recitations are made, are understood to beillustrative rather than limiting, and it is also understood that suchsubstitutions are encompassed even when no illustrative examples ofsubstitutions are recited, For example, wherever one or more of the Ab1light chain polypeptides is recited, e.g. any of SEQ ID NO: 2, 20, 647,648, 649, 650, 651, 660, 666, 699, 702, 706, or 709, another Ab1 lightchain polypeptide may be substituted unless the context indicatesotherwise. Similarly, wherever one of the Ab1 heavy chain polypeptidesis recited, e.g. any of SEQ ID NO: 3, 18, 19, 652, 653, 654, 655, 656,657, 661, 664, 665, 657, 658, 704, or 708, another Ab1 heavy chainpolypeptide may be substituted unless the context indicates otherwise.Likewise, wherever one of the Ab1 light chain polynucleotides isrecited, e.g. any of SEQ ID NO:10, 662, 698, 701, or 705, another Ab1light chain polynucleotide may be substituted unless the contextindicates otherwise. Similarly, wherever one of the Ab1 heavy chainpolynucleotides is recited, e.g. any of SEQ ID NO:11, 663, 700, 703, or707, another Ab1 heavy chain polynucleotide may be substituted unlessthe context indicates otherwise. Additionally, recitation of any memberof any of the following groups is understood to encompass substitutionby any other member of the group, as follows: Ab2 Light chainpolypeptides (SEQ ID NO:21 and 667); Ab2 Light chain polynucleotides(SEQ ID NO:29 and 669); Ab2 Heavy chain polypeptides (SEQ ID NO:22 and668); Ab2 Heavy chain polynucleotides (SEQ ID NO:30 and 670); Ab3 Lightchain polypeptides (SEQ ID NO:37 and 671); Ab3 Light chainpolynucleotides (SEQ ID NO:45 and 673); Ab3 Heavy chain polypeptides(SEQ ID NO:38 and 672); Ab3 Heavy chain polynucleotides (SEQ ID NO:46and 674); Ab4 Light chain polypeptides (SEQ ID NO:53 and 675); Ab4 Lightchain polynucleotides (SEQ ID NO:61 and 677); Ab4 Heavy chainpolypeptides (SEQ ID NO:54 and 676); Ab4 Heavy chain polynucleotides(SEQ ID NO:62 and 678); Ab5 Light chain polypeptides (SEQ ID NO:69 and679); Ab5 Light chain polynucleotides (SEQ ID NO:77 and 681); Ab5 Heavychain polypeptides (SEQ ID NO:70 and 680); Ab5 Heavy chainpolynucleotides (SEQ ID NO:78 and 682); Ab6 Light chain polypeptides(SEQ ID NO:85 and 683); Ab6 Light chain polynucleotides (SEQ ID NO:93and 685); Ab6 Heavy chain polypeptides (SEQ ID NO:86 and 684); Ab6 Heavychain polynucleotides (SEQ ID NO:94 and 686); Ab7 Light chainpolypeptides (SEQ ID NO:101, 119, 687, 693); Ab7 Light chainpolynucleotides (SEQ ID NO:109 and 689); Ab7 Heavy chain polypeptides(SEQ ID NO:102, 117, 118, 688, 691, and 692); Ab7 Heavy chainpolynucleotides (SEQ ID NO:110 and 690); Ab1 Light Chain CDR1polynucleotides (SEQ ID NO:12 and 694); Ab1 Light Chain CDR3polynucleotides (SEQ ID NO:14 and 695); Ab1 Heavy Chain CDR2polynucleotides (SEQ ID NO:16 and 696) and Ab1 Heavy Chain CDR3polynucleotides (SEQ ID NO:17 and 697).

SEQ ID NO: 660 (Which was included in the sequence listingfiled with U.S. application Ser. No. 12/153,612 filed May21, 2008 as SEQ ID NO: 2)MDTRAPTQLLGLLLLWLPGARCAYDMTQTPASVSAAVGGTVTIKCQASQSINNELSWYQQKPGQRPKLLIYRASTLASGVSSRFKGSGSGTEFTLTISDLECADAATYYCQQGYSLRN IDNASEQ ID NO: 661 (Which was included in the sequence listingfiled with U.S. application Ser. No. 12/153,612 filed May21, 2008 as SEQ ID NO: 3)METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTASGFSLSNYYVTWVRQAPGKGLEWIGIIYGSDETAYATWAIGRFTISKTSTTVDLKMTSLTAADTATYFCARDDSSD WDAKFNLSEQ ID NO: 662 (Which was included in the sequence listingfiled with U.S. application Ser. No. 12/153,612 filed May21, 2008 as SEQ ID NO: 10)ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGCCTATGATATGACCCAGACTCCAGCCTCGGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAAGTGCCAGGCCAGTCAGAGCATTAACAATGAATTATCCTGGTATCAGCAGAAACCAGGGCAGCGTCCCAAGCTCCTGATCTATAGGGCATCCACTCTGGCATCTGGGGTCTCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAACAGGGTTATAGTCTGAGGAAT ATTGATAATGCTSEQ ID NO: 663 (Which was included in the sequence listingfiled with U.S. application Ser. No. 12/153,612 filed May21, 2008 as SEQ ID NO: 11)ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGCCTCTGGATTCTCCCTCAGTAACTACTACGTGACCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGAATCATTTATGGTAGTGATGAAACGGCCTACGCGACCTGGGCGATAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGAAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTCTGTGCCAGAGATGATAGTAGTGACTGGGATGCAAAATTTAACTTGSEQ ID NO: 664 (Which was SEQ ID NO: 18 of U.S. ProvisionalApplication Serial No. 60/924,550 filed May 21, 2007)EVQLVESGGGLVQPGGSLRLSCAASGFSLSNYYVTWVRQAPGKGLEWVGIIYGSDETAYATWAIGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDDSSDWDAKFNLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKSEQ ID NO: 665 (Which was SEQ ID NO: 19 of U.S. ProvisionalApplication Serial No. 60/924,550 filed May 21, 2007)EVQLVESGGGLVQPGGSLRLSCAASGFSLSNYYVTWVRQAPGKGLEWVGIIYGSDETAYATSAIGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDDSSDWDAKFNLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKSEQ ID NO: 666 (Which was SEQ ID NO: 20 of U.S. ProvisionalApplication Serial No. 60/924,550 filed May 21, 2007)IQMTQSPSSLSASVGDRVTITCQASQSINNELSWYQQKPGKAPKLLIYRASTLASGVPSRFSGSGSGTDFTLTISSLQPDDFATYYCQQGYSLRNIDNAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO: 667 (Which was included in the sequence listingfiled with U.S. application Ser. No. 12/153,612 filed May21, 2008 as SEQ ID NO: 21)MDTRAPTQLLGLLLLWLPGARCAYDMTQTPASVEVAVGGTVTINCQASETIYSWLSWYQQKPGQPPKLLIYQASDLASGVPSRFSGSGAGTEYTLTISGVQCDDAATYYCQQGYSGSN VDNVSEQ ID NO: 668 (Which was included in the sequence listingfiled with U.S. application Ser. No. 12/153,612 filed May21, 2008 as SEQ ID NO: 22)METGLRWLLLVAVLKGVQCQEQLKESGGRLVTPGTPLTLTCTASGFSLNDHAMGWVRQAPGKGLEYIGFINSGGSARYASWAEGRFTISRTSTTVDLKMTSLTTEDTATYFCVRGGAV WSIHSFDPSEQ ID NO: 669 (Which was included in the sequence listingfiled with U.S. application Ser. No. 12/153,612 filed May21, 2008 as SEQ ID NO: 29)ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGCCTATGATATGACCCAGACTCCAGCCTCTGTGGAGGTAGCTGTGGGAGGCACAGTCACCATCAATTGCCAGGCCAGTGAGACCATTTACAGTTGGTTATCCTGGTATCAGCAGAAGCCAGGGCAGCCTCCCAAGCTCCTGATCTACCAGGCATCCGATCTGGCATCTGGGGTCCCATCGCGATTCAGCGGCAGTGGGGCTGGGACAGAGTACACTCTCACCATCAGCGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGTCAACAGGGTTATAGTGGTAGTAAT GTTGATAATGTTSEQ ID NO: 670 (Which was included in the sequence listingfiled with U.S. application Ser. No. 12/153,612 filed May21, 2008 as SEQ ID NO: 30)ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGGAGCAGCTGAAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTTACCTGCACAGCCTCTGGATTCTCCCTCAATGACCATGCAATGGGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATACATCGGATTCATTAATAGTGGTGGTAGCGCACGCTACGCGAGCTGGGCAGAAGGCCGATTCACCATCTCCAGAACCTCGACCACGGTGGATCTGAAAATGACCAGTCTGACAACCGAGGACACGGCCACCTATTTCTGTGTCAGAGGGGGTGCTGTTTGGAGTATTCATAGTTTTGATCCCSEQ ID NO: 671 (Which was included in the sequence listingfiled with U.S. application Ser. No. 12/153,612 filed May21, 2008 as SEQ ID NO: 37)MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSPVSAAVGGTVSISCQASQSVYDNNYLSWFQQKPGQPPKLLIYGASTLASGVPSRFVGSGSGTQFTLTITDVQCDDAATYYCAGVYDD DSDNASEQ ID NO: 672 (Which was included in the sequence listingfiled with U.S. application Ser. No. 12/153,612 filed May21, 2008 as SEQ ID NO: 38)METGLRWLLLVAVLKGVQCQSLEESGGRLVTPGTPLTLTCTASGFSLSVYYMNWVRQAPGKGLEWIGFITMSDNINYASWAKGRFTISKTSTTVDLKMTSPTTEDTATYFCARSRGWG TMGRLDLSEQ ID NO: 673 (Which was included in the sequence listingfiled with U.S. application Ser. No. 12/153,612 filed May21, 2008 as SEQ ID NO: 45)ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCCGCCGTGCTGACCCAGACTCCATCTCCCGTGTCTGCAGCTGTGGGAGGCACAGTCAGCATCAGTTGCCAGGCCAGTCAGAGTGTTTATGACAACAACTACTTATCCTGGTTTCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGGTGCATCCACTCTGGCATCTGGGGTCCCATCGCGGTTCGTGGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCACAGACGTGCAGTGTGACGATGCTGCCACTTACTATTGTGCAGGCGTTTATGATGATGATAGTGATAATGCCSEQ ID NO: 674 (Which was included in the sequence listingfiled with U.S. application Ser. No. 12/153,612 filed May21, 2008 as SEQ ID NO: 46)ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTGGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACCCCTGGGACACCCCTGACACTCACCTGCACAGCCTCTGGATTCTCCCTCAGTGTCTACTACATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGATTCATTACAATGAGTGATAATATAAATTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGAAAATGACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGGAGTCGTGGCTGGGGTACAATGGGTCGGTTGGATCTCSEQ ID NO: 675 (Which was included in the sequence listingfiled with U.S. application Ser. No. 12/153,612 filed May21, 2008 as SEQ ID NO: 53)MDTRAPTQLLGLLLLWLPGAICDPVLTQTPSPVSAPVGGTVSISCQASQSVYENNYLSWFQQKPGQPPKLLIYGASTLDSGVPSRFKGSGSGTQFTLTITDVQCDDAATYYCAGVYDD DSDDASEQ ID NO: 676 (Which was included in the sequence listingfiled with U.S. application Ser. No. 12/153,612 filed May21, 2008 as SEQ ID NO: 54)METGLRWLLLVAVLKGVQCQEQLKESGGGLVTPGGTLTLTCTASGFSLNAYYMNWVRQAPGKGLEWIGFITLNNNVAYANWAKGRFTFSKTSTTVDLKMTSPTPEDTATYFCARSRGW GAMGRLDLSEQ ID NO: 677 (Which was included in the sequence listingfiled with U.S. application Ser. No. 12/153,612 filed May21, 2008 as SEQ ID NO: 61)ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCATATGTGACCCTGTGCTGACCCAGACTCCATCTCCCGTATCTGCACCTGTGGGAGGCACAGTCAGCATCAGTTGCCAGGCCAGTCAGAGTGTTTATGAGAACAACTATTTATCCTGGTTTCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGGTGCATCCACTCTGGATTCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATTACAGACGTGCAGTGTGACGATGCTGCCACTTACTATTGTGCAGGCGTTTATGATGATGATAGTGATGATGCCSEQ ID NO: 678 (Which was included in the sequence listingfiled with U.S. application Ser. No. 12/153,612 filed May21, 2008 as SEQ ID NO: 62)ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTGGCTGTGCTCAAAGGTGTCCAGTGTCAGGAGCAGCTGAAGGAGTCCGGAGGAGGCCTGGTAACGCCTGGAGGAACCCTGACACTCACCTGCACAGCCTCTGGATTCTCCCTCAATGCCTACTACATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGATTCATTACTCTGAATAATAATGTAGCTTACGCGAACTGGGCGAAAGGCCGATTCACCTTCTCCAAAACCTCGACCACGGTGGATCTGAAAATGACCAGTCCGACACCCGAGGACACGGCCACCTATTTCTGTGCCAGGAGTCGTGGCTGGGGTGCAATGGGTCGGTTGGATCTCSEQ ID NO: 679 (Which was included in the sequence listingfiled with U.S. application Ser. No. 12/153,612 filed May21, 2008 as SEQ ID NO: 69)MDTRAPTQLLGLLLLWLPGATFAQVLTQTPSPVSAAVGGTVTINCQASQSVDDNNWLGWYQQKRGQPPKYLIYSASTLASGVPSRFKGSGSGTQFTLTISDLECDDAATYYCAGGFSG NIFASEQ ID NO: 680 (Which was included in the sequence listingfiled with U.S. application Ser. No. 12/153,612 filed May21, 2008 as SEQ ID NO: 70)METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTVSGFSLSSYAMSWVRQAPGKGLEWIGIIGGFGTTYYATWAKGRFTISKTSTTVDLRITSPTTEDTATYFCARGGPGN GGDISEQ ID NO: 681 (Which was included in the sequence listingfiled with U.S. application Ser. No. 12/153,612 filed May21, 2008 as SEQ ID NO: 77)ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCCCAAGTGCTGACCCAGACTCCATCGCCTGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAACTGCCAGGCCAGTCAGAGTGTTGATGATAACAACTGGTTAGGCTGGTATCAGCAGAAACGAGGGCAGCCTCCCAAGTACCTGATCTATTCTGCATCCACTCTGGCATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGACCTGGAGTGTGACGATGCTGCCACTTACTACTGTGCAGGCGGTTTTAGTGGT AATATCTTTGCTSEQ ID NO: 682 (Which was included in the sequence listingfiled with U.S. application Ser. No. 12/153,612 filed May21, 2008 as SEQ ID NO: 78)ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGTCTCTGGCTTCTCCCTCAGTAGCTATGCAATGAGCTGGGTCCGCCAGGCTCCAGGAAAGGGGCTGGAGTGGATCGGAATCATTGGTGGTTTTGGTACCACATACTACGCGACCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGAGAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGGTGGTCCTGGTAAT GGTGGTGACATCSEQ ID NO: 683 (Which was included in the sequence listingfiled with U.S. application Ser. No. 12/153,612 filed May21, 2008 as SEQ ID NO: 85)MDTRAPTQLLGLLLLWLPGATFAAVLTQTPSPVSVPVGGTVTIKCQSSQSVYNNFLSWYQQKPGQPPKLLIYQASKLASGVPDRFSGSGSGTQFTLTISGVQCDDAATYYCLGGYDDD ADNASEQ ID NO: 684 (Which was included in the sequence listingfiled with U.S. application Ser. No. 12/153,612 filed May21, 2008 as SEQ ID NO: 86)METGLRWLLLVAVLKGVQCQSVEESGGRLVTPGTPLTLTCTVSGIDLSDYAMSWVRQAPGKGLEWIGIIYAGSGSTWYASWAKGRFTISKTSTTVDLKITSPTTEDTATYFCARDGYD DYGDFDRLDLSEQ ID NO: 685 (Which was included in the sequence listingfiled with U.S. application Ser. No. 12/153,612 filed May21, 2008 as SEQ ID NO: 93)ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCACATTTGCAGCCGTGCTGACCCAGACACCATCGCCCGTGTCTGTACCTGTGGGAGGCACAGTCACCATCAAGTGCCAGTCCAGTCAGAGTGTTTATAATAATTTCTTATCGTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTACCAGGCATCCAAACTGGCATCTGGGGTCCCAGATAGGTTCAGCGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGGCGTGCAGTGTGACGATGCTGCCACTTACTACTGTCTAGGCGGTTATGATGATGAT GCTGATAATGCTSEQ ID NO: 686 (Which was included in the sequence listingfiled with U.S. application Ser. No. 12/153,612 filed May21, 2008 as SEQ ID NO: 94)ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCAGTGTCAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACGCTCACCTGCACAGTCTCTGGAATCGACCTCAGTGACTATGCAATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGAATCATTTATGCTGGTAGTGGTAGCACATGGTACGCGAGCTGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGATGGATACGATGACTATGGTGATTTCGATCGATTGGATCTCSEQ ID NO: 687 (Which was included in the sequence listingfiled with U.S. application Ser. No. 12/153,612 filed May21, 2008 as SEQ ID NO: 101)MDTRAPTQLLGLLLLWLPGARCAYDMTQTPASVSAAVGGTVTIKCQASQSINNELSWYQQKSGQRPKLLIYRASTLASGVSSRFKGSGSGTEFTLTISDLECADAATYYCQQGYSLRN IDNASEQ ID NO: 688 (Which was included in the sequence listingfiled with U.S. application Ser. No. 12/153,612 filed May21, 2008 as SEQ ID NO: 102)METGLRWLLLVAVLSGVQCQSLEESGGRLVTPGTPLTLTCTASGFSLSNYYMTWVRQAPGKGLEWIGMIYGSDETAYANWAIGRFTISKTSTTVDLKMTSLTAADTATYFCARDDSSD WDAKFNLSEQ ID NO: 689 (Which was included in the sequence listingfiled with U.S. application Ser. No. 12/153,612 filed May21, 2008 as SEQ ID NO: 109)ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGTGCCAGATGTGCCTATGATATGACCCAGACTCCAGCCTCGGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAAATGCCAGGCCAGTCAGAGCATTAACAATGAATTATCCTGGTATCAGCAGAAATCAGGGCAGCGTCCCAAGCTCCTGATCTATAGGGCATCCACTCTGGCATCTGGGGTCTCATCGCGGTTCAAAGGCAGTGGATCTGGGACAGAGTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAACAGGGTTATAGTCTGAGGAAT ATTGATAATGCTSEQ ID NO: 690 (Which was included in the sequence listingfiled with U.S. application Ser. No. 12/153,612 filed May21, 2008 as SEQ ID NO: 110)ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCTCAGGTGTCCAGTGTCAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGCCTCTGGATTCTCCCTCAGTAACTACTACATGACCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGAATGATTTATGGTAGTGATGAAACAGCCTACGCGAACTGGGCGATAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGAAAATGACCAGTCTGACAGCCGCGGACACGGCCACCTATTTCTGTGCCAGAGATGATAGTAGTGACTGGGATGCAAAATTTAACTTGSEQ ID NO: 691 (Which was SEQ ID NO: 117 of U.S. ProvisionalApplication Serial No. 60/924,550 filed May 21, 2007)EVQLVESGGGLVQPGGSLRLSCAASGFSLSNYYMTWVRQAPGKGLEWVGMIYGSDETAYANWAIGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDDSSDWDAKFNLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKSEQ ID NO: 692 (Which was SEQ ID NO: 118 of U.S. ProvisionalApplication Serial No. 60/924,550 filed May 21, 2007)EVQLVESGGGLVQPGGSLRLSCAASGFSLSNYYMTWVRQAPGKGLEWVGMIYGSDETAYANSAIGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDDSSDWDAKFNLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKSEQ ID NO: 693 (Which was SEQ ID NO: 119 of U.S. ProvisionalApplication Serial No. 60/924,550 filed May 21, 2007)DIQMTQSPSTLSASVGDRVTITCQASQSINNELSWYQQKPGKAPKLLIYRASTLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQGYSLRNIDNAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO: 698 (Exemplary polynucleotide encoding theVariable Light Chain polypeptide of SEQ ID NO: 699)GCTATCCAGATGACCCAGTCTCCTTCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTAACAATGAGTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAGGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGACTTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTCTGAGGAACATTGATAATGCTTTCGGCGGAGGGACCAAGGTGGAAATCAAACGTACGSEQ ID NO: 699 (Exemplary Variable Light Chain polypeptide sequence)AIQMTQSPSSLSASVGDRVTITCQASQSINNELSWYQQKPGKAPKLLIYRASTLASGVPSRFSGSGSGTDFTLTISSLQPDDFATYYCQQGYSLRNIDNAFGGGTKVEIKRTSEQ ID NO: 700 (Exemplary polynucleotide encoding theVariable Heavy Chain polypeptide of SEQ ID NO: 657)GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCCTCAGTAACTACTACGTGACCTGGGTCCGTCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCGGCATCATCTATGGTAGTGATGAAACCGCCTACGCTACCTCCGCTATAGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTTCAAATGAACAGCCTGAGAGCTGAGGACACTGCTGTGTATTACTGTGCTAGAGATGATAGTAGTGACTGGGATGCAAAGTTCAACTTGTGGGGCCAAGGGACCCTCGTCACCGTC TCGAGCSEQ ID NO: 701 (Exemplary polynucleotide encoding the Fulllength Light chain (without signal peptide) polypeptide ofSEQ ID NO: 702)GCTATCCAGATGACCCAGTCTCCTTCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTAACAATGAGTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAGGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGACTTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTCTGAGGAACATTGATAATGCTTTCGGCGGAGGGACCAAGGTGGAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGT GTSEQ ID NO: 702 (Exemplary Full length Light chain (withoutsignal peptide) polypeptide sequence)AIQMTQSPSSLSASVGDRVTITCQASQSINNELSWYQQKPGKAPKLLIYRASTLASGVPSRFSGSGSGTDFTLTISSLQPDDFATYYCQQGYSLRNIDNAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO: 703 (Exemplary polynucleotide encoding the Fulllength Heavy chain (without signal peptide) polypeptide ofSEQ ID NO: 704)GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCCTCAGTAACTACTACGTGACCTGGGTCCGTCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCGGCATCATCTATGGTAGTGATGAAACCGCCTACGCTACCTCCGCTATAGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTTCAAATGAACAGCCTGAGAGCTGAGGACACTGCTGTGTATTACTGTGCTAGAGATGATAGTAGTGACTGGGATGCAAAGTTCAACTTGTGGGGCCAAGGGACCCTCGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACGCCAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAASEQ ID NO: 704 (Exemplary Full length Heavy chain (withoutsignal peptide) polypeptide sequence)EVQLVESGGGLVQPGGSLRLSCAASGFSLSNYYVTWVRQAPGKGLEWVGIIYGSDETAYATSAIGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDDSSDWDAKFNLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKSEQ ID NO: 705 (Exemplary polynucleotide encoding the Fulllength Light chain (with signal peptide) polypeptide of SEQ ID NO: 706)ATGAAGTGGGTAACCTTTATTTCCCTTCTGTTTCTCTTTAGCAGCGCTTATTCCGCTATCCAGATGACCCAGTCTCCTTCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCAGGCCAGTCAGAGCATTAACAATGAGTTATCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATAGGGCATCCACTCTGGCATCTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAGACTTCACTCTCACCATCAGCAGCCTGCAGCCTGATGATTTTGCAACTTATTACTGCCAACAGGGTTATAGTCTGAGGAACATTGATAATGCTTTCGGCGGAGGGACCAAGGTGGAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGTSEQ ID NO: 706 (Exemplary Full length Light chain (withsignal peptide) polypeptide sequence)MKWVTFISLLFLFSSAYSAIQMTQSPSSLSASVGDRVTITCQASQSINNELSWYQQKPGKAPKLLIYRASTLASGVPSRFSGSGSGTDFTLTISSLQPDDFATYYCQQGYSLRNIDNAFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECSEQ ID NO: 707 (Exemplary polynucleotide encoding the Fulllength Heavy chain (with signal peptide) polypeptide of SEQ ID NO: 708)ATGAAGTGGGTAACCTTTATTTCCCTTCTGTTTCTCTTTAGCAGCGCTTATTCCGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCCTCAGTAACTACTACGTGACCTGGGTCCGTCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCGGCATCATCTATGGTAGTGATGAAACCGCCTACGCTACCTCCGCTATAGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACCCTGTATCTTCAAATGAACAGCCTGAGAGCTGAGGACACTGCTGTGTATTACTGTGCTAGAGATGATAGTAGTGACTGGGATGCAAAGTTCAACTTGTGGGGCCAAGGGACCCTCGTCACCGTCTCGAGCGCCTCCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAGAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACGCCAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAASEQ ID NO: 708 (Exemplary Full length Heavy chain (withsignal peptide) polypeptide sequence)MKWVTFISLLFLFSSAYSEVQLVESGGGLVQPGGSLRLSCAASGFSLSNYYVTWVRQAPGKGLEWVGIIYGSDETAYATSAIGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDDSSDWDAKFNLWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKExemplary Embodiments of Polynucleotides Encoding CDR Sequences

SEQ ID NO: 694 (Exemplary polynucleotide encodingthe Light Chain CDR1 polypeptide of SEQ ID NO: 4)CAGGCCAGTCAGAGCATTAACAATGAGTTATCCSEQ ID NO: 695 (Exemplary polynucleotide encodingthe Light Chain CDR3 polypeptide of SEQ ID NO: 6)CAACAGGGTTATAGTCTGAGGAACATTGATAATGCTSEQ ID NO: 696 (Exemplary polynucleotide encodingthe Heavy Chain CDR2 polypeptide of SEQ ID NO: 120)ATCATCTATGGTAGTGATGAAACCGCCTACGCTACCTCCGCTATAGGCSEQ ID NO: 697 (Exemplary polynucleotide encodingthe Heavy Chain CDR3 polypeptide of SEQ ID NO: 9)GATGATAGTAGTGACTGGGATGCAAAGTTCAACTTGScreening Assays

The invention also includes screening assays designed to assist in theidentification of diseases and disorders associated with IL-6 inpatients exhibiting symptoms of an IL-6 associated disease or disorder.

In one embodiment of the invention, the anti-IL-6 antibodies of theinvention, or IL-6 binding fragments thereof, are used to detect thepresence of IL-6 in a biological sample obtained from a patientexhibiting symptoms of a disease or disorder associated with IL-6. Thepresence of IL-6, or elevated levels thereof when compared topre-disease levels of IL-6 in a comparable biological sample, may bebeneficial in diagnosing a disease or disorder associated with IL-6.

Another embodiment of the invention provides a diagnostic or screeningassay to assist in diagnosis of diseases or disorders associated withIL-6 in patients exhibiting symptoms of an IL-6 associated disease ordisorder identified herein, comprising assaying the level of IL-6expression in a biological sample from said patient using apost-translationally modified anti-IL-6 antibody or binding fragmentthereof. The anti-IL-6 antibody or binding fragment thereof may bepost-translationally modified to include a detectable moiety such as setforth previously in the disclosure.

The IL-6 level in the biological sample is determined using a modifiedanti-IL-6 antibody or binding fragment thereof as set forth herein, andcomparing the level of IL-6 in the biological sample against a standardlevel of IL-6 (e.g., the level in normal biological samples). Theskilled clinician would understand that some variability may existbetween normal biological samples, and would take that intoconsideration when evaluating results.

The above-recited assay may also be useful in monitoring a disease ordisorder, where the level of IL-6 obtained in a biological sample from apatient believed to have an IL-6 associated disease or disorder iscompared with the level of IL-6 in prior biological samples from thesame patient, in order to ascertain whether the IL-6 level in saidpatient has changed with, for example, a treatment regimen.

The invention is also directed to a method of in vivo imaging whichdetects the presence of cells which express IL-6 comprisingadministering a diagnostically effective amount of a diagnosticcomposition. Said in vivo imaging is useful for the detection andimaging of IL-6 expressing tumors or metastases and IL-6 expressinginflammatory sites, for example, and can be used as part of a planningregimen for design of an effective cancer or arthritis treatmentprotocol. The treatment protocol may include, for example, one or moreof radiation, chemotherapy, cytokine therapy, gene therapy, and antibodytherapy, as well as an anti-IL-6 antibody or fragment thereof.

A skilled clinician would understand that a biological sample includes,but is not limited to, sera, plasma, urine, saliva, mucous, pleuralfluid, synovial fluid and spinal fluid.

Methods of Ameliorating or Reducing Symptoms of, or Treating, orPreventing, Diseases and Disorders Associated with, IL-6

In another embodiment of the invention, anti-IL-6 antibodies describedherein, or fragments thereof, are useful for ameliorating or reducingthe symptoms of, or treating, or preventing, diseases and disordersassociated with IL-6. Anti-IL-6 antibodies described herein, orfragments thereof, can also be administered in a therapeuticallyeffective amount to patients in need of treatment of diseases anddisorders associated with IL-6 in the form of a pharmaceuticalcomposition as described in greater detail below.

In one embodiment of the invention, anti-IL-6 antibodies describedherein, or fragments thereof, are useful for ameliorating or reducingthe symptoms of, or treating, or preventing, diseases and disordersassociated with fatigue. Diseases and disorders associated with fatigueinclude, but are not limited to, general fatigue, exercise-inducedfatigue, cancer-related fatigue, inflammatory disease-related fatigueand chronic fatigue syndrome. See, for example, Esper D H, et al, Thecancer cachexia syndrome: a review of metabolic and clinicalmanifestations, Nutr Clin Pract., 2005 August; 20 (4):369-76; Vgontzas AN, et al, IL-6 and its circadian secretion in humans,Neuroimmunomodulation, 2005; 12(3):131-40; Robson-Ansley, P J, et al,Acute interleukin-6 administration impairs athletic performance inhealthy, trained male runners, Can J Appl Physiol., 2004 August;29(4):411-8; Shephard R J., Cytokine responses to physical activity,with particular reference to IL-6: sources, actions, and clinicalimplications, Crit Rev Immunol., 2002; 22(3):165-82; Arnold, M C, et al,Using an interleukin-6 challenge to evaluate neuropsychologicalperformance in chronic fatigue syndrome, Psychol Med., 2002 August;32(6):1075-89; Kurzrock R., The role of cytokines in cancer-relatedfatigue, Cancer, 2001 Sep. 15; 92(6 Suppl):1684-8; Nishimoto N, et al,Improvement in Castleman's disease by humanized anti-interleukin-6receptor antibody therapy, Blood, 2000 Jan. 1; 95 (1):56-61; Vgontzas AN, et al, Circadian interleukin-6 secretion and quantity and depth ofsleep, J Clin Endocrinol Metab., 1999 August; 84(8):2603-7; andSpath-Schwalbe E, et al, Acute effects of recombinant human interleukin6 on endocrine and central nervous sleep functions in healthy men, JClin Endocrinol Metab., 1998 May; 83(5):1573-9; the disclosures of eachof which are herein incorporated by reference in their entireties.

In a preferred embodiment of the invention, anti-IL-6 antibodiesdescribed herein, or fragments thereof, are useful for ameliorating orreducing the symptoms of, or treating, or preventing, cachexia. Diseasesand disorders associated with cachexia include, but are not limited to,cancer-related cachexia, cardiac-related cachexia, respiratory-relatedcachexia, renal-related cachexia and age-related cachexia. See, forexample, Barton, B E., Interleukin-6 and new strategies for thetreatment of cancer, hyperproliferative diseases and paraneoplasticsyndromes, Expert Opin Ther Targets, 2005 August; 9(4):737-52; Zaki M H,et al, CNTO 328, a monoclonal antibody to IL-6, inhibits humantumor-induced cachexia in nude mice, Int J Cancer, 2004 Sep. 10;111(4):592-5; Trikha M, et al, Targeted anti-interleukin-6 monoclonalantibody therapy for cancer: a review of the rationale and clinicalevidence, Clin Cancer Res., 2003 Oct. 15; 9(13):4653-65; Lelli G, et al,Treatment of the cancer anorexia-cachexia syndrome: a criticalreappraisal, J Chemother., 2003 June; 15(3):220-5; Argiles J M, et al,Cytokines in the pathogenesis of cancer cachexia, Curr Opin Clin NutrMetab Care, 2003 July; 6(4):401-6; Barton B E., IL-6-like cytokines andcancer cachexia: consequences of chronic inflammation, Immunol Res.,2001; 23(1):41-58; Yamashita J I, et al, Medroxyprogesterone acetate andcancer cachexia: interleukin-6 involvement, Breast Cancer, 2000;7(2):130-5; Yeh S S, et al, Geriatric cachexia: the role of cytokines,Am J Clin Nutr., 1999 August; 70(2):183-97; Strassmann G, et al,Inhibition of experimental cancer cachexia by anti-cytokine andanti-cytokine-receptor therapy, Cytokines Mol Ther., 1995 June;1(2):107-13; Fujita J, et al, Anti-interleukin-6 receptor antibodyprevents muscle atrophy in colon-26 adenocarcinoma-bearing mice withmodulation of lysosomal and ATP-ubiquitin-dependent proteolyticpathways, Int J Cancer, 1996 Nov. 27; 68(5):637-43; Tsujinaka T, et al,Interleukin 6 receptor antibody inhibits muscle atrophy and modulatesproteolytic systems in interleukin 6 transgenic mice, J Clin Invest.,1996 Jan. 1; 97(1):244-9; Emilie D, et al, Administration of ananti-interleukin-6 monoclonal antibody to patients with acquiredimmunodeficiency syndrome and lymphoma: effect on lymphoma growth and onB clinical Symptoms, Blood, 1994 Oct. 15; 84 (8):2472-9; and StrassmannG, et al, Evidence for the involvement of interleukin 6 in experimentalcancer cachexia, J Clin Invest., 1992 May; 89(5):1681-4; the disclosuresof each of which are herein incorporated by reference in theirentireties.

In another embodiment of the invention, anti-IL-6 antibodies describedherein, or fragments thereof, are useful for ameliorating or reducingthe symptoms of, or treating, or preventing, autoimmune diseases anddisorders. Diseases and disorders associated with autoimmunity include,but are not limited to, rheumatoid arthritis, systemic lupuserythematosis (SLE), systemic juvenile idiopathic arthritis, psoriasis,psoriatic arthropathy, ankylosing spondylitis, inflammatory boweldisease (IBD), polymyalgia rheumatica, giant cell arteritis, autoimmunevasculitis, graft versus host disease (GVHD), Sjogren's syndrome, adultonset Still's disease. In a preferred embodiment of the invention,humanized anti-IL-6 antibodies described herein, or fragments thereof,are useful for ameliorating or reducing the symptoms of, or treating, orpreventing, rheumatoid arthritis and systemic juvenile idiopathicarthritis. See, for example, Nishimoto N., Clinical studies in patientswith Castleman's disease, Crohn's disease, and rheumatoid arthritis inJapan, Clin Rev Allergy Immunol., 2005 June; 28(3):221-30; Nishimoto N,et al, Treatment of rheumatoid arthritis with humanizedanti-interleukin-6 receptor antibody: a multicenter, double-blind,placebo-controlled trial, Arthritis Rheum., 2004 June; 50(6):1761-9;Choy E., Interleukin 6 receptor as a target for the treatment ofrheumatoid arthritis, Ann Rheum Dis., 2003 November; 62 Suppl 2:ii68-9;Nishimoto N, et al, Toxicity, pharmacokinetics, and dose-finding studyof repetitive treatment with the humanized anti-interleukin 6 receptorantibody MRA in rheumatoid arthritis. Phase I/II clinical study, JRheumatol., 2003 July; 30(7):1426-35; Mihara M, et al, Humanizedantibody to human interleukin-6 receptor inhibits the development ofcollagen arthritis in cynomolgus monkeys, Clin Immunol., 2001 March;98(3):319-26; Nishimoto N, et al, Anti-interleukin 6 receptor antibodytreatment in rheumatic disease, Ann Rheum Dis., 2000 November; 59 Suppl1:i21-7; Tackey E, et al, Rationale for interleukin-6 blockade insystemic lupus erythematosus, Lupus, 2004; 13(5):339-43; Finck B K, etal, Interleukin 6 promotes murine lupus in NZB/NZW F1 mice, J ClinInvest., 1994 August; 94 (2):585-91; Kitani A, et al, Autostimulatoryeffects of IL-6 on excessive B cell differentiation in patients withsystemic lupus erythematosus: analysis of IL-6 production and IL-6Rexpression, Clin Exp Immunol., 1992 April; 88(1):75-83; Stuart R A, etal, Elevated serum interleukin-6 levels associated with active diseasein systemic connective tissue disorders, Clin Exp Rheumatol., 1995January-February; 13 (1):17-22; Mihara M, et al, IL-6 receptor blockageinhibits the onset of autoimmune kidney disease in NZB/W F1 mice, ClinExp Immunol., 1998 June; 12(3):397-402; Woo P, et al, Open label phaseII trial of single, ascending doses of MRA in Caucasian children withsevere systemic juvenile idiopathic arthritis: proof of principle of theefficacy of IL-6 receptor blockade in this type of arthritis anddemonstration of prolonged clinical improvement, Arthritis Res Ther.,2005; 7(6):RI281-8. Epub 2005 Sep. 15; Yokota S, et al, Clinical studyof tocilizumab in children with systemic-onset juvenile idiopathicarthritis, Clin Rev Allergy Immunol., 2005 June; 28(3):231-8; Yokota S,et al, Therapeutic efficacy of humanized recombinant anti-interleukin-6receptor antibody in children with systemic-onset juvenile idiopathicarthritis, Arthritis Rheum., 2005 March; 52(3):818-25; de Benedetti F,et al, Targeting the interleukin-6 receptor: a new treatment forsystemic juvenile idiopathic arthritis?, Arthritis Rheum., 2005 March;52(3):687-93; De Benedetti F, et al, Is systemic juvenile rheumatoidarthritis an interleukin 6 mediated disease?, J Rheumatol., 1998February; 25(2):203-7; Ishihara K, et al, IL-6 in autoimmune disease andchronic inflammatory proliferative disease, Cytokine Growth Factor Rev.,2002 August-October; 13 (4-5):357-68; Gilhar A, et al, In vivo effectsof cytokines on psoriatic skin grafted on nude mice: involvement of thetumor necrosis factor (TNF) receptor, Clin Exp Immunol., 1996 October;106(1):134-42; Spadaro A, et al, Interleukin-6 and soluble interleukin-2receptor in psoriatic arthritis: correlations with clinical andlaboratory parameters, Clin Exp Rheumatol., 1996 July-August; 14(4):413-6; Ameglio F, et al, Interleukin-6 and tumor necrosis factorlevels decrease in the suction blister fluids of psoriatic patientsduring effective therapy, Dermatology, 1994; 189(4):359-63; Wendling D,et al, Combination therapy of anti-CD4 and anti-IL-6 monoclonalantibodies in a case of severe spondylarthropathy, Br J Rheumatol., 1996December; 35(12):1330; Gratacos J, et al, Serum cytokines (IL-6,TNF-alpha, IL-1 beta and IFN-gamma) in ankylosing spondylitis: a closecorrelation between serum IL-6 and disease activity and severity, Br JRheumatol., 1994 October; 33(10):927-31; Ito H., Treatment of Crohn'sdisease with anti-IL-6 receptor antibody, J Gastroenterol., 2005 March;40 Suppl 16:32-4; Ito H, et al, A pilot randomized trial of a humananti-interleukin-6 receptor monoclonal antibody in active Crohn'sdisease, Gastroenterology, 2004 April; 126(4):989-96; discussion 947;Ito H., IL-6 and Crohn's disease, Curr Drug Targets Inflamm Allergy,2003 June; 2(2):12530; Ito H, et al, Anti-IL-6 receptor monoclonalantibody inhibits leukocyte recruitment and promotes T-cell apoptosis ina murine model of Crohn's disease, J Gastroenterol., 2002 November; 37Suppl 14:56-61; Ito H., Anti-interleukin-6 therapy for Crohn's disease,Curr Pharm Des., 2003; 9(4):295-305; Salvarani C, et al, Acute-phasereactants and the risk of relapse/recurrence in polymyalgia rheumatica:a prospective follow-up study, Arthritis Rheum., 2005 Feb. 15;53(1):33-8; Roche N E, et al, Correlation of interleukin-6 productionand disease activity in polymyalgia rheumatica and giant cell arteritis,Arthritis Rheum., 1993 September; 36(9):1286-94; Gupta M, et al,Cytokine modulation with immune gamma-globulin in peripheral blood ofnormal children and its implications in Kawasaki disease treatment, JClin Immunol., 2001 May; 21(3):193-9; Noris M, et al, Interleukin-6 andRANTES in Takayasu arteritis: a guide for therapeutic decisions?,Circulation, 1999 Jul. 6; 100(1):55-60; Besbas N, et al, The role ofcytokines in Henoch Schonlein purpura, Scand J Rheumatol., 1997;26(6):456-60; Hirohata S, et al, Cerebrospinal fluid interleukin-6 inprogressive Neuro-Behcet's syndrome, Clin Immunol Immunopathol., 1997January; 82(1):12-7; Yamakawa Y, et al, Interleukin-6 (IL-6) in patientswith Behcet's disease, J Dermatol Sci., 1996 March; 11(3):189-95; Kim DS., Serum interleukin-6 in Kawasaki disease, Yonsei Med J., 1992 June;33(2):183-8; Lange, A., et al, Cytokines, adhesion molecules (E-selectinand VCAM-1) and graft-versus-host disease, Arch. Immunol Ther Exp.,1995, 43(2):99-105; Tanaka, J., et al, Cytokine gene expression afterallogeneic bone marrow transplantation, Leuk. Lymphoma, 199516(5-6):413-418; Dickenson, A M, et al, Predicting outcome inhematological stem cell transplantation, Arch Immunol Ther Exp., 200250(6):371-8; Zeiser, R, et al, Immunopathogenesis of acutegraft-versus-host disease: implications for novel preventive andtherapeutic strategies, Ann Hematol., 2004 83(9):551-65; Dickinson, A M,et al, Genetic polymorphisms predicting the outcome of bone marrowtransplants, Br. J Haematol., 2004 127(5):479-90; and Scheinberg M A, etal, Interleukin 6: a possible marker of disease activity in adult onsetStill's disease, Clin Exp Rheumatol., 1996 November-December; 14(6):653-5, the disclosures of each of which are herein incorporated byreference in their entireties.

In another embodiment of the invention, anti-IL-6 antibodies describedherein, or fragments thereof, are useful for ameliorating or reducingthe symptoms of, or treating, or preventing, diseases and disordersassociated with the skeletal system. Diseases and disorders associatedwith the skeletal system include, but are not limited to,osteoarthritis, osteoporosis and Paget's disease of bone. In a preferredembodiment of the invention, humanized anti-IL-6 antibodies describedherein, or fragments thereof, are useful for ameliorating or reducingthe symptoms of, or treating, or preventing, osteoarthritis. See, forexample, Malemud C J., Cytokines as therapeutic targets forosteoarthritis, BioDrugs, 2004; 18(1):23-35; Westacott C I, et al,Cytokines in osteoarthritis: mediators or markers of joint destruction?,Semin Arthritis Rheum., 1996 February; 25(4):254-72; Sugiyama T.,Involvement of interleukin-6 and prostaglandin E2 in particularosteoporosis of postmenopausal women with rheumatoid arthritis, J BoneMiner Metab., 2001; 19(2):89-96; Abrahamsen B, et al, Cytokines and boneloss in a 5-year longitudinal study-hormone replacement therapysuppresses serum soluble interleukin-6 receptor and increasesinterleukin-1-receptor antagonist: the Danish Osteoporosis PreventionStudy, J Bone Miner Res., 2000 August; 15(8):1545-54; Straub R H, et al,Hormone replacement therapy and interrelation between seruminterleukin-6 and body mass index in postmenopausal women: apopulation-based study, J Clin Endocrinol Metab., 2000 March;85(3):1340-4; Manolagas S C, The role of IL-6 type cytokines and theirreceptors in bone, Ann N Y Acad Sci., 1998 May 1; 840:194-204; Ershler WB, et al, Immunologic aspects of osteoporosis, Dev Comp Immunol., 1997November-December; 21(6):487-99; Jilka R L, et al, Increased osteoclastdevelopment after estrogen loss: mediation by interleukin-6, Science,1992 Jul. 3; 257(5066):88-91; Kallen K J, et al, New developments inIL-6 dependent biology and therapy: where do we stand and what are theoptions?, Expert Opin Investig Drugs, 1999 September; 8(9):1327-49;Neale S D, et al, The influence of serum cytokines and growth factors onosteoclast formation in Paget's disease, QJM, 2002 April; 95 (4):233-40;Roodman G D, Osteoclast function In Paget's disease and multiplemyeloma, Bone, 1995 August; 17(2 Suppl):575-61S; Hoyland J A, et al,Interleukin-6, IL-6 receptor, and IL-6 nuclear factor gene expression inPaget's disease, J Bone Miner Res., 1994 January; 9(1):75-80; andRoodman G D, et al, Interleukin 6. A potential autocrine/paracrinefactor in Paget's disease of bone, J Clin Invest., 1992 January;89(1):46-52; the disclosures of each of which are herein incorporated byreference in their entireties.

In another embodiment of the invention, anti-IL-6 antibodies describedherein, or fragments thereof, are useful for ameliorating or reducingthe symptoms of, or treating, or preventing, diseases and disordersassociated with cancer. Diseases and disorders associated with cancerinclude, but are not limited to, multiple myeloma, Hodgkin's lymphoma,non-Hodgkin's lymphoma, prostate cancer, leukemia, renal cell cancer,multicentric Castleman's disease, ovarian cancer, drug resistance incancer chemotherapy and cancer chemotherapy toxicity. See, for example,Hirata T, et al, Humanized anti-interleukin-6 receptor monoclonalantibody induced apoptosis of fresh and cloned human myeloma cells invitro, Leuk Res., 2003 April; 27(4):343-9, Bataille R, et al, Biologiceffects of anti-interleukin-6 murine monoclonal antibody in advancedmultiple myeloma, Blood, 1995 Jul. 15; 86 (2):685-91; Goto H, et al,Mouse anti-human interleukin-6 receptor monoclonal antibody inhibitsproliferation of fresh human myeloma cells in vitro, Jpn J Cancer Res.,1994 September; 85(9):958-65; Klein B, et al, Murine anti-interleukin-6monoclonal antibody therapy for a patient with plasma cell leukemia,Blood, 1991 Sep. 1; 78(5):1198-204; Mauray S, et al, Epstein-Barrvirus-dependent lymphoproliferative disease: critical role of IL-6, EurJ Immunol., 2000 July; 30(7):2065-73; Tsunenari T, et al, New xenograftmodel of multiple myeloma and efficacy of a humanized antibody againsthuman interleukin-6 receptor, Blood, 1997 Sep. 15; 90(6):2437-44; EmilieD, et al, Interleukin-6 production in high-grade B lymphomas:correlation with the presence of malignant immunoblasts in acquiredimmunodeficiency syndrome and in human immunodeficiencyvirus-seronegative patients, Blood, 1992 Jul. 15; 80(2):498-504; EmilieD, et al, Administration of an anti-interleukin-6 monoclonal antibody topatients with acquired immunodeficiency syndrome and lymphoma: effect onlymphoma growth and on B clinical Symptoms, Blood, 1994 Oct. 15;84(8):2472-9; Smith P C, et al, Anti-interleukin-6 monoclonal antibodyinduces regression of human prostate cancer xenografts in nude mice,Prostate, 2001 Jun. 15; 48(1):47-53; Smith P C, et al, Interleukin-6 andprostate cancer progression, Cytokine Growth Factor Rev., 2001 March;12(1):33-40; Chung T D, et al, Characterization of the role of IL-6 inthe progression of prostate cancer, Prostate, 1999 Feb. 15;38(3):199-207; Okamoto M, et al, Interleukin-6 as a paracrine andautocrine growth factor in human prostatic carcinoma cells in vitro,Cancer Res., 1997 Jan. 1; 57(1):141-6; Reittie J E, et al, Interleukin-6inhibits apoptosis and tumor necrosis factor induced proliferation ofB-chronic lymphocytic leukemia, Leuk Lymphoma, 1996 June; 22(1-2):83-90,follow 186, color plate VI; Sugiyama H, et al, The expression of IL-6and its related genes in acute leukemia, Leuk Lymphoma, 1996 March;21(1-2):49-52; Bataille R, et al, Effects of an anti-interleukin-6(IL-6) murine monoclonal antibody in a patient with acute monoblasticleukemia, Med Oncol Tumor Pharmacother., 1993; 10(4):185-8; Kedar I, etal, Thalidomide reduces serum C-reactive protein and interleukin-6 andinduces response to IL-2 in a fraction of metastatic renal cell cancerpatients who failed IL-2-based therapy, Int J Cancer, 2004 Jun. 10;110(2):260-5; Angelo L S, Talpaz M, Kurzrock R, Autocrine interleukin-6production in renal cell carcinoma: evidence for the involvement of p53,Cancer Res., 2002 Feb. 1; 62(3):932-40; Nishimoto N, Humanizedanti-interleukin-6 receptor antibody treatment of multicentric Castlemandisease, Blood, 2005 Oct. 15; 106(8):2627-32, Epub 2005 Jul. 5; KatsumeA, et al, Anti-interleukin 6 (IL-6) receptor antibody suppressesCastleman's disease like symptoms emerged in IL-6 transgenic mice,Cytokine, 2002 Dec. 21; 20(6):304-11; Nishimoto N, et al, Improvement inCastleman's disease by humanized anti-interleukin-6 receptor antibodytherapy, Blood, 2000 Jan. 1; 95(1):56-61; Screpanti I, Inactivation ofthe IL-6 gene prevents development of multicentric Castleman's diseasein C/EBP beta-deficient mice, J Exp Med., 1996 Oct. 1; 184(4):1561-6;Hsu S M, et al, Expression of interleukin-6 in Castleman's disease, HumPathol., 1993 August; 24(8):833-9; Yoshizaki K, et al, Pathogenicsignificance of interleukin-6 (IL 6/BSF-2) in Castleman's disease,Blood, 1989 September; 74(4):1360-7; Nilsson M B, et al, Interleukin-6,secreted by human ovarian carcinoma cells, is a potent proangiogeniccytokine, Cancer Res., 2005 Dec. 1; 65(23):10794-800; Toutirais O, etal, Constitutive expression of TGF-betal, interleukin-6 andinterleukin-8 by tumor cells as a major component of immune escape inhuman ovarian carcinoma, Eur Cytokine Netw., 2003 October-December;14(4):246-55; Obata N H, et al, Effects of interleukin 6 on in vitrocell attachment, migration and invasion of human ovarian carcinoma,Anticancer Res., 1997 January-February; 17 (1A):337-42; Dedoussis G V,et al, Endogenous interleukin 6 conveys resistance tocis-diamminedichloroplatinum-mediated apoptosis of the K562 humanleukemic cell line, Exp Cell Res., 1999 Jun. 15; 249(2):269-78;Borsellino N, et al, Blocking signaling through the Gp130 receptor chainby interleukin-6 and oncostatin M inhibits PC-3 cell growth andsensitizes the tumor cells to etoposide and cisplatin-mediatedcytotoxicity, Cancer, 1999 Jan. 1; 85(1):134-44; Borsellino N, et al,Endogenous interleukin 6 is a resistance factor forcis-diamminedichloroplatinum and etoposide-mediated cytotoxicity ofhuman prostate carcinoma cell lines, Cancer Res., 1995 Oct. 15;55(20):4633-9; Mizutani Y, et al, Sensitization of human renal cellcarcinoma cells to cis-diamminedichloroplatinum(II) by anti-interleukin6 monoclonal antibody or anti-interleukin 6 receptor monoclonalantibody; Cancer Res., 1995 Feb. 1; 55(3):590-6; Yusuf R Z, et al,Paclitaxel resistance: molecular mechanisms and pharmacologicmanipulation, Curr Cancer Drug Targets, 2003 February; 3(1):1-19; DuanZ, et al, Overexpression of IL-6 but not IL-8 increases paclitaxelresistance of U-20S human osteosarcoma cells, Cytokine, 2002 Mar. 7;17(5):234-42; Conze D, et al, Autocrine production of interleukin 6causes multidrug resistance in breast cancer cells, Cancer Res., 2001Dec. 15; 61(24):8851-8; Rossi J F, et al, Optimizing the use ofanti-interleukin-6 monoclonal antibody with dexamethasone and 140 mg/m2of melphalan in multiple myeloma: results of a pilot study includingbiological aspects, Bone Marrow Transplant, 2005 November; 36(9):771-9;and Tonini G, et al, Oxaliplatin may induce cytokine-release syndrome incolorectal cancer patients, J Biol Regul Homeost Agents, 2002April-June; 16 (2):105-9; the disclosures of each of which are hereinincorporated by reference in their entireties.

In another embodiment of the invention, anti-IL-6 antibodies describedherein, or fragments thereof, are useful for ameliorating or reducingthe symptoms of, or treating, or preventing, ischemic heart disease,atherosclerosis, obesity, diabetes, asthma, multiple sclerosis,Alzheimer's disease, cerebrovascular disease, fever, acute phaseresponse, allergies, anemia, anemia of inflammation (anemia of chronicdisease), hypertension, depression, depression associated with a chronicillness, thrombosis, thrombocytosis, acute heart failure, metabolicsyndrome, miscarriage, obesity, chronic prostatitis, glomerulonephritis,pelvic inflammatory disease, reperfusion injury, and transplantrejection. See, for example, Tzoulaki I, et al, C-reactive protein,interleukin-6, and soluble adhesion molecules as predictors ofprogressive peripheral atherosclerosis in the general population:Edinburgh Artery Study, Circulation, 2005 Aug. 16; 112(7):976-83, Epub2005 Aug. 8; Rattazzi M, et al, C-reactive protein and interleukin-6 invascular disease: culprits or passive bystanders?, J Hypertens., 2003October; 21(10):1787-803; Ito T, et al, HMG-CoA reductase inhibitorsreduce interleukin-6 synthesis in human vascular smooth muscle cells,Cardiovasc Drugs Ther., 2002 March; 16(2):121-6; Stenvinkel P, et al,Mortality, malnutrition, and atherosclerosis in ESRD: what is the roleof interleukin-6?, Kidney Int Suppl., 2002 May; (80):103-8; Yudkin J S,et al, Inflammation, obesity, stress and coronary heart disease: isinterleukin-6 the link?, Atherosclerosis, 2000 February; 148(2):209-14;Huber S A, et al, Interleukin-6 exacerbates early atherosclerosis inmice, Arterioscler Thromb Vasc Biol., 1999 October; 19(10):2364-7; KadoS, et al, Circulating levels of interleukin-6, its soluble receptor andinterleukin-6/interleukin-6 receptor complexes in patients with type 2diabetes mellitus, Acta Diabetol., 1999 June; 36(1-2):67-72; Sukovich DA, et al, Expression of interleukin-6 in atherosclerotic lesions of maleApoE-knockout mice: inhibition by 17 beta-estradiol, Arterioscler ThrombVasc Biol., 1998 September; 8(9):1498-505; Klover P J, et al,Interleukin-6 depletion selectively improves hepatic insulin action inobesity, Endocrinology, 2005 August; 146(8):3417-27, Epub 2005 Apr. 21;Lee Y H, et al, The evolving role of inflammation in obesity and themetabolic syndrome, Curr Diab Rep., 2005 February; 5(1):70-5; Diamant M,et al, The association between abdominal visceral fat and carotidstiffness is mediated by circulating inflammatory markers inuncomplicated type 2 diabetes, J Clin Endocrinol Metab., 2005 March;90(3):1495-501, Epub 2004 Dec. 21; Bray G A, Medical consequences ofobesity, J Clin Endocrinol Metab., 2004 June; 89(6):2583 9; Klover P J,et al, Chronic exposure to interleukin-6 causes hepatic insulinresistance in mice, Diabetes, 2003 November; 52 (11):2784-9; Yudkin J S,et al, Inflammation, obesity, stress and coronary heart disease: isinterleukin-6 the link?, Atherosclerosis, 2000 February; 148(2):209-14;Doganci A, et al, Pathological role of IL-6 in the experimental allergicbronchial asthma in mice, Clin Rev Allergy Immunol., 2005 June;28(3):257-70; Doganci A, et al, The IL-6R alpha chain controls lungCD4+CD25+ Treg development and function during allergic airwayinflammation in vivo, J Clin Invest., 2005 February; 115(2):313 25,(Erratum in: J Clin Invest., 2005 May; 115(5):1388, Lehr, Hans A[added]); Stelmasiak Z, et al, IL 6 and sIL-6R concentration in thecerebrospinal fluid and serum of MS patients, Med Sci Monit., 2001September-October; 7(5):914-8; Tilgner J, et al, Continuousinterleukin-6 application in vivo via macroencapsulation ofinterleukin-6-expressing COS-7 cells induces massive gliosis, Glia, 2001September; 35(3):234-45, Brunello A G, et al, Astrocytic alterations ininterleukin-6 Soluble interleukin-6 receptor alpha double-transgenicmice, Am J Pathol., 2000 November; 157(5):1485-93; Hampel H, et al,Pattern of interleukin-6 receptor complex immunoreactivity betweencortical regions of rapid autopsy normal and Alzheimer's disease brain,Eur Arch Psychiatry Clin Neurosci., 2005 August; 255(4):269-78, Epub2004 Nov. 26; Cacquevel M, et al, Cytokines in neuroinflammation andAlzheimer's disease, Curr Drug Targets, 2004 August; 5(6):529-34;Quintanilla R A, et al, Interleukin 6 induces Alzheimer-typephosphorylation of tau protein by deregulating the cdk5/p35 pathway, ExpCell Res., 2004 Apr. 15; 295 (1):245-57; Gadient R A, et al,Interleukin-6 (IL-6)—a molecule with both beneficial and destructivepotentials, Prog Neurobiol., 1997 August; 52(5):379-90; Hull M, et al,Occurrence of interleukin-6 in cortical plaques of Alzheimer's diseasepatients may precede transformation of diffuse into neuritic plaques,Ann N Y Acad Sci., 1996 Jan. 17; 777:205-12; Rallidis L S, et al,Inflammatory markers and in-hospital mortality in acute ischaemicstroke, Atherosclerosis, 2005 Dec. 30; Emsley H C, et al, Interleukin-6and acute ischaemic stroke, Acta Neurol Scand., 2005 October;112(4):273-4; Smith C J, et al, Peak plasma interleukin-6 and otherperipheral markers of inflammation in the first week of ischaemic strokecorrelate with brain infarct volume, stroke severity and long-termoutcome, BMC Neurol., 2004 Jan. 15; 4:2; Vila N, et al, Proinflammatorycytokines and early neurological worsening in ischemic stroke, Stroke,2000 October; 31(10):2325-9; and Tarkowski E, et al, Early intrathecalproduction of interleukin-6 predicts the size of brain lesion in stroke,Stroke, 1995 August; 26(8):1393-8; the disclosures of each of which areherein incorporated by reference in their entireties.

In another embodiment of the invention, anti-IL-6 antibodies describedherein, or fragments thereof, are useful for ameliorating or reducingthe symptoms of, or treating, or preventing, diseases and disordersassociated with cytokine storm. Diseases and disorders associated withcytokine storm include, but are not limited to, graft versus hostdisease (GVHD), avian influenza, smallpox, pandemic influenza, adultrespiratory distress syndrome (ARDS), severe acute respiratory syndrome(SARS), sepsis, and systemic inflammatory response syndrome (SIRS). See,for example, Cecil, R. L., Goldman, L., & Bennett, J. C. (2000). Ceciltextbook of medicine. Philadelphia: W.B. Saunders; Ferrara J L, et al.,Cytokine storm of graft-versus-host disease: a critical effector rolefor interleukin-1, Transplant Proc. 1993 February; 25(1 Pt 2):1216-7;Osterholm M T, Preparing for the Next Pandemic, N Engl J Med. 2005 May5; 352(18):1839-42; Huang K J, et al., An interferon-gamma-relatedcytokine storm in SARS patients, J Med Virol. 2005 February;75(2):185-94; and Cheung C Y, et al., Induction of proinflammatorycytokines in human macrophages by influenza A (H5N1) viruses: amechanism for the unusual severity of human disease? Lancet. 2002 Dec.7; 360(9348):1831-7.

In another embodiment of the invention, anti-IL-6 antibodies describedherein, or fragments thereof, are useful as a wakefulness aid.

Administration

In one embodiment of the invention, the anti-IL-6 antibodies describedherein, or IL-6 binding fragments thereof, as well as combinations ofsaid antibody fragments, are administered to a subject at aconcentration of between about 0.1 and 20 mg/kg, such as about 0.4mg/kg, about 0.8 mg/kg, about 1.6 mg/kg, or about 4 mg/kg, of bodyweight of recipient subject. In a preferred embodiment of the invention,the anti-IL-6 antibodies described herein, or IL-6 binding fragmentsthereof, as well as combinations of said antibody fragments, areadministered to a subject at a concentration of about 0.4 mg/kg of bodyweight of recipient subject. In a preferred embodiment of the invention,the anti-IL-6 antibodies described herein, or IL-6 binding fragmentsthereof, as well as combinations of said antibody fragments, areadministered to a recipient subject with a frequency of once everytwenty-six weeks or less, such as once every sixteen weeks or less, onceevery eight weeks or less, or once every four weeks, or less.

It is understood that the effective dosage may depend on recipientsubject attributes, such as, for example, age, gender, pregnancy status,body mass index, lean body mass, condition or conditions for which thecomposition is given, other health conditions of the recipient subjectthat may affect metabolism or tolerance of the composition, levels ofIL-6 in the recipient subject, and resistance to the composition (forexample, arising from the patient developing antibodies against thecomposition). A person of skill in the art would be able to determine aneffective dosage and frequency of administration through routineexperimentation, for example guided by the disclosure herein and theteachings in Goodman, L. S., Gilman, A., Brunton, L. L., Lazo, J. S., &Parker, K. L. (2006). Goodman & Gilman's the pharmacological basis oftherapeutics. New York: McGraw-Hill; Howland, R. D., Mycek, M. J.,Harvey, R. A., Champe, P. C., & Mycek, M. J. (2006). Pharmacology.Lippincott's illustrated reviews. Philadelphia: Lippincott Williams &Wilkins; and Golan, D. E. (2008). Principles of pharmacology: thepathophysiologic basis of drug therapy. Philadelphia, Pa., [etc.]:Lippincott Williams & Wilkins.

In another embodiment of the invention, the anti-IL-6 antibodiesdescribed herein, or IL-6 binding fragments thereof, as well ascombinations of said antibody fragments, are administered to a subjectin a pharmaceutical formulation.

A “pharmaceutical composition” refers to a chemical or biologicalcomposition suitable for administration to a mammal. Such compositionsmay be specifically formulated for administration via one or more of anumber of routes, including but not limited to buccal, epicutaneous,epidural, inhalation, intraarterial, intracardial,intracerebroventricular, intradermal, intramuscular, intranasal,intraocular, intraperitoneal, intraspinal, intrathecal, intravenous,oral, parenteral, rectally via an enema or suppository, subcutaneous,subdermal, sublingual, transdermal, and transmucosal. In addition,administration can occur by means of injection, powder, liquid, gel,drops, or other means of administration.

In one embodiment of the invention, the anti-IL-6 antibodies describedherein, or IL-6 binding fragments thereof, as well as combinations ofsaid antibody fragments, may be optionally administered in combinationwith one or more active agents. Such active agents include analgesic,antipyretic, anti-inflammatory, antibiotic, antiviral, and anti-cytokineagents. Active agents include agonists, antagonists, and modulators ofTNF-α, IL-2, IL-4, IL-6, IL-10, IL-12, IL-13, IL-18, IFN-α, IFN-γ, BAFF,CXCL13, IP-10, VEGF, EPO, EGF, HRG, Hepatocyte Growth Factor (HGF),Hepcidin, including antibodies reactive against any of the foregoing,and antibodies reactive against any of their receptors. Active agentsalso include 2-Arylpropionic acids, Aceclofenac, Acemetacin,Acetylsalicylic acid (Aspirin), Alclofenac, Alminoprofen, Amoxiprin,Ampyrone, Arylalkanoic acids, Azapropazone, Benorylate/Benorilate,Benoxaprofen, Bromfenac, Carprofen, Celecoxib, Choline magnesiumsalicylate, Clofezone, COX-2 inhibitors, Dexibuprofen, Dexketoprofen,Diclofenac, Diflunisal, Droxicam, Ethenzamide, Etodolac, Etoricoxib,Faislamine, fenamic acids, Fenbufen, Fenoprofen, Flufenamic acid,Flunoxaprofen, Flurbiprofen, Ibuprofen, Ibuproxam, Indometacin,Indoprofen, Kebuzone, Ketoprofen, Ketorolac, Lornoxicam, Loxoprofen,Lumiracoxib, Magnesium salicylate, Meclofenamic acid, Mefenamic acid,Meloxicam, Metamizole, Methyl salicylate, Mofebutazone, Nabumetone,Naproxen, N-Arylanthranilic acids, Oxametacin, Oxaprozin, Oxicams,Oxyphenbutazone, Parecoxib, Phenazone, Phenylbutazone, Phenylbutazone,Piroxicam, Pirprofen, profens, Proglumetacin, Pyrazolidine derivatives,Rofecoxib, Salicyl salicylate, Salicylamide, Salicylates,Sulfinpyrazone, Sulindac, Suprofen, Tenoxicam, Tiaprofenic acid,Tolfenamic acid, Tolmetin, and Valdecoxib. Antibiotics include Amikacin,Aminoglycosides, Amoxicillin, Ampicillin, Ansamycins, Arsphenamine,Azithromycin, Azlocillin, Aztreonam, Bacitracin, Carbacephem,Carbapenems, Carbenicillin, Cefaclor, Cefadroxil, Cefalexin, Cefalothin,Cefalotin, Cefamandole, Cefazolin, Cefdinir, Cefditoren, Cefepime,Cefixime, Cefoperazone, Cefotaxime, Cefoxitin, Cefpodoxime, Cefprozil,Ceftazidime, Ceftibuten, Ceftizoxime, Ceftobiprole, Ceftriaxone,Cefuroxime, Cephalosporins, Chloramphenicol, Cilastatin, Ciprofloxacin,Clarithromycin, Clindamycin, Cloxacillin, Colistin, Co-trimoxazole,Dalfopristin, Demeclocycline, Dicloxacillin, Dirithromycin, Doripenem,Doxycycline, Enoxacin, Ertapenem, Erythromycin, Ethambutol,Flucloxacillin, Fosfomycin, Furazolidone, Fusidic acid, Gatifloxacin,Geldanamycin, Gentamicin, Glycopeptides, Herbimycin, Imipenem,Isoniazid, Kanamycin, Levofloxacin, Lincomycin, Linezolid, Lomefloxacin,Loracarbef, Macrolides, Mafenide, Meropenem, Meticillin, Metronidazole,Mezlocillin, Minocycline, Monobactams, Moxifloxacin, Mupirocin,Nafcillin, Neomycin, Netilmicin, Nitrofurantoin, Norfloxacin, Ofloxacin,Oxacillin, Oxytetracycline, Paromomycin, Penicillin, Penicillins,Piperacillin, Platensimycin, Polymyxin B, Polypeptides, Prontosil,Pyrazinamide, Quinolones, Quinupristin, Rifampicin, Rifampin,Roxithromycin, Spectinomycin, Streptomycin, Sulfacetamide,Sulfamethizole, Sulfanilimide, Sulfasalazine, Sulfisoxazole,Sulfonamides, Teicoplanin, Telithromycin, Tetracycline, Tetracyclines,Ticarcillin, Tinidazole, Tobramycin, Trimethoprim,Trimethoprim-Sulfamethoxazole, Troleandomycin, Trovafloxacin, andVancomycin. Active agents also include Aldosterone, Beclometasone,Betamethasone, Corticosteroids, Cortisol, Cortisone acetate,Deoxycorticosterone acetate, Dexamethasone, Fludrocortisone acetate,Glucocorticoids, Hydrocortisone, Methylprednisolone, Prednisolone,Prednisone, Steroids, and Triamcinolone. Antiviral agents includeabacavir, aciclovir, acyclovir, adefovir, amantadine, amprenavir, anantiretroviral fixed dose combination, an antiretroviral synergisticenhancer, arbidol, atazanavir, atripla, brivudine, cidofovir, combivir,darunavir, delavirdine, didanosine, docosanol, edoxudine, efavirenz,emtricitabine, enfuvirtide, entecavir, entry inhibitors, famciclovir,fomivirsen, fosamprenavir, foscarnet, fosfonet, fusion inhibitor,ganciclovir, gardasil, ibacitabine, idoxuridine, imiquimod, imunovir,indinavir, inosine, integrase inhibitor, interferon, interferon type I,interferon type II, interferon type III, lamivudine, lopinavir,loviride, maraviroc, MK-0518, moroxydine, nelfinavir, nevirapine,nexavir, nucleoside analogues, oseltamivir, penciclovir, peramivir,pleconaril, podophyllotoxin, protease inhibitor, reverse transcriptaseinhibitor, ribavirin, rimantadine, ritonavir, saquinavir, stavudine,tenofovir, tenofovir disoproxil, tipranavir, trifluridine, trizivir,tromantadine, truvada, valaciclovir, valganciclovir, vicriviroc,vidarabine, viramidine, zalcitabine, zanamivir, and zidovudine. Anysuitable combination of these active agents is also contemplated.

A “pharmaceutical excipient” or a “pharmaceutically acceptableexcipient” is a carrier, usually a liquid, in which an activetherapeutic agent is formulated. In one embodiment of the invention, theactive therapeutic agent is a humanized antibody described herein, orone or more fragments thereof. The excipient generally does not provideany pharmacological activity to the formulation, though it may providechemical and/or biological stability, and release characteristics.Exemplary formulations can be found, for example, in Remington'sPharmaceutical Sciences, 19^(th) Ed., Grennaro, A., Ed., 1995 which isincorporated by reference.

As used herein “pharmaceutically acceptable carrier” or “excipient”includes any and all solvents, dispersion media, coatings, antibacterialand antifungal agents, isotonic and absorption delaying agents that arephysiologically compatible. In one embodiment, the carrier is suitablefor parenteral administration. Alternatively, the carrier can besuitable for intravenous, intraperitoneal, intramuscular, or sublingualadministration. Pharmaceutically acceptable carriers include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. The use of such media and agents for pharmaceuticallyactive substances is well known in the art. Except insofar as anyconventional media or agent is incompatible with the active compound,use thereof in the pharmaceutical compositions of the invention iscontemplated. Supplementary active compounds can also be incorporatedinto the compositions.

Pharmaceutical compositions typically must be sterile and stable underthe conditions of manufacture and storage. The invention contemplatesthat the pharmaceutical composition is present in lyophilized form. Thecomposition can be formulated as a solution, microemulsion, liposome, orother ordered structure suitable to high drug concentration. The carriercan be a solvent or dispersion medium containing, for example, water,ethanol, polyol (for example, glycerol, propylene glycol, and liquidpolyethylene glycol), and suitable mixtures thereof. The inventionfurther contemplates the inclusion of a stabilizer in the pharmaceuticalcomposition.

In many cases, it will be preferable to include isotonic agents, forexample, sugars, polyalcohols such as mannitol, sorbitol, or sodiumchloride in the composition. Prolonged absorption of the injectablecompositions can be brought about by including in the composition anagent which delays absorption, for example, monostearate salts andgelatin. Moreover, the alkaline polypeptide can be formulated in a timerelease formulation, for example in a composition which includes a slowrelease polymer. The active compounds can be prepared with carriers thatwill protect the compound against rapid release, such as a controlledrelease formulation, including implants and microencapsulated deliverysystems. Biodegradable, biocompatible polymers can be used, such asethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen,polyorthoesters, polylactic acid and polylactic, polyglycolic copolymers(PLG). Many methods for the preparation of such formulations are knownto those skilled in the art.

For each of the recited embodiments, the compounds can be administeredby a variety of dosage forms. Any biologically-acceptable dosage formknown to persons of ordinary skill in the art, and combinations thereof,are contemplated. Examples of such dosage forms include, withoutlimitation, reconstitutable powders, elixirs, liquids, solutions,suspensions, emulsions, powders, granules, particles, microparticles,dispersible granules, cachets, inhalants, aerosol inhalants, patches,particle inhalants, implants, depot implants, injectables (includingsubcutaneous, intramuscular, intravenous, and intradermal), infusions,and combinations thereof.

The above description of various illustrated embodiments of theinvention is not intended to be exhaustive or to limit the invention tothe precise form disclosed. While specific embodiments of, and examplesfor, the invention are described herein for illustrative purposes,various equivalent modifications are possible within the scope of theinvention, as those skilled in the relevant art will recognize. Theteachings provided herein of the invention can be applied to otherpurposes, other than the examples described above.

These and other changes can be made to the invention in light of theabove detailed description. In general, in the following claims, theterms used should not be construed to limit the invention to thespecific embodiments disclosed in the specification and the claims.Accordingly, the invention is not limited by the disclosure, but insteadthe scope of the invention is to be determined entirely by the followingclaims.

The invention may be practiced in ways other than those particularlydescribed in the foregoing description and examples. Numerousmodifications and variations of the invention are possible in light ofthe above teachings and, therefore, are within the scope of the appendedclaims.

Certain teachings related to methods for obtaining a clonal populationof antigen-specific B cells were disclosed in U.S. Provisional patentapplication No. 60/801,412, filed May 19, 2006, the disclosure of whichis herein incorporated by reference in its entirety.

Certain teachings related to humanization of rabbit-derived monoclonalantibodies and preferred sequence modifications to maintain antigenbinding affinity were disclosed in International Application No.PCT/US2008/064432, entitled “Novel Rabbit Antibody Humanization Methodand Humanized Rabbit Antibodies”, filed May 21, 2008, the disclosure ofwhich is herein incorporated by reference in its entirety.

Certain teachings related to producing antibodies or fragments thereofusing mating competent yeast and corresponding methods were disclosed inU.S. patent application Ser. No. 11/429,053, filed May 8, 2006, (U.S.Patent Application Publication No. US2006/0270045), the disclosure ofwhich is herein incorporated by reference in its entirety.

Certain teachings related to IL-6 antibodies, methods of producingantibodies or fragments thereof using mating competent yeast andcorresponding methods were disclosed in U.S. provisional patentapplication No. 60/924,550, filed May 21, 2007, the disclosure of whichis herein incorporated by reference in its entirety.

Certain anti-IL-6 antibody polynucleotides and polypeptides aredisclosed in the sequence listing accompanying this patent applicationfiling, and the disclosure of said sequence listing is hereinincorporated by reference in its entirety.

The entire disclosure of each document cited (including patents, patentapplications, journal articles, abstracts, manuals, books, or otherdisclosures) in the Background of the Invention, Detailed Description,and Examples is herein incorporated by reference in their entireties.

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the subject invention, and are not intended to limit thescope of what is regarded as the invention. Efforts have been made toensure accuracy with respect to the numbers used (e.g. amounts,temperature, concentrations, etc.) but some experimental errors anddeviations should be allowed for. Unless otherwise indicated, parts areparts by weight, molecular weight is average molecular weight,temperature is in degrees centigrade; and pressure is at or nearatmospheric.

EXAMPLES Example 1 Production of Enriched Antigen-Specific B CellAntibody Culture

Panels of antibodies are derived by immunizing traditional antibody hostanimals to exploit the native immune response to a target antigen ofinterest. Typically, the host used for immunization is a rabbit or otherhost that produces antibodies using a similar maturation process andprovides for a population of antigen-specific B cells producingantibodies of comparable diversity, e.g., epitopic diversity. Theinitial antigen immunization can be conducted using complete Freund'sadjuvant (CFA), and the subsequent boosts effected with incompleteadjuvant. At about 50-60 days after immunization, preferably at day 55,antibody titers are tested, and the Antibody Selection (ABS) process isinitiated if appropriate titers are established. The two key criteriafor ABS initiation are potent antigen recognition and function-modifyingactivity in the polyclonal sera.

At the time positive antibody titers are established, animals aresacrificed and B cell sources isolated. These sources include: thespleen, lymph nodes, bone marrow, and peripheral blood mononuclear cells(PBMCs). Single cell suspensions are generated, and the cell suspensionsare washed to make them compatible for low temperature long termstorage. The cells are then typically frozen.

To initiate the antibody identification process, a small fraction of thefrozen cell suspensions are thawed, washed, and placed in tissue culturemedia. These suspensions are then mixed with a biotinylated form of theantigen that was used to generate the animal immune response, andantigen-specific cells are recovered using the Miltenyi magnetic beadcell selection methodology. Specific enrichment is conducted usingstreptavidin beads. The enriched population is recovered and progressedin the next phase of specific B cell isolation.

Example 2 Production of Clonal, Antigen-Specific B Cell-ContainingCulture

Enriched B cells produced according to Example 1 are then plated atvarying cell densities per well in a 96 well microtiter plate.Generally, this is at 50, 100, 250, or 500 cells per well with 10 platesper group. The media is supplemented with 4% activated rabbit T cellconditioned media along with 50K frozen irradiated EL4B feeder cells.These cultures are left undisturbed for 5-7 days at which timesupernatant-containing secreted antibody is collected and evaluated fortarget properties in a separate assay setting. The remaining supernatantis left intact, and the plate is frozen at −70° C. Under theseconditions, the culture process typically results in wells containing amixed cell population that comprises a clonal population ofantigen-specific B cells, i.e., a single well will only contain a singlemonoclonal antibody specific to the desired antigen.

Example 3 Screening of Antibody Supernatants for Monoclonal Antibody ofDesired Specificity and/or Functional Properties

Antibody-containing supernatants derived from the well containing aclonal antigen-specific B cell population produced according to Example2 are initially screened for antigen recognition using ELISA methods.This includes selective antigen immobilization (e.g., biotinylatedantigen capture by streptavidin coated plate), non-specific antigenplate coating, or alternatively, through an antigen build-up strategy(e.g., selective antigen capture followed by binding partner addition togenerate a heteromeric protein-antigen complex). Antigen-positive wellsupernatants are then optionally tested in a function-modifying assaythat is strictly dependant on the ligand. One such example is an invitro protein-protein interaction assay that recreates the naturalinteraction of the antigen ligand with recombinant receptor protein.Alternatively, a cell-based response that is ligand dependent and easilymonitored (e.g., proliferation response) is utilized. Supernatant thatdisplays significant antigen recognition and potency is deemed apositive well. Cells derived from the original positive well are thentransitioned to the antibody recovery phase.

Example 4 Recovery of Single, Antibody-Producing B Cell of DesiredAntigen Specificity

Cells are isolated from a well that contains a clonal population ofantigen-specific B cells (produced according to Example 2 or 3), whichsecrete a single antibody sequence. The isolated cells are then assayedto isolate a single, antibody-secreting cell. Dynal streptavidin beadsare coated with biotinylated target antigen under buffered medium toprepare antigen-containing microbeads compatible with cell viability.Next antigen-loaded beads, antibody-producing cells from the positivewell, and a fluorescein isothiocyanate (FITC)-labeled anti-host H&L IgGantibody (as noted, the host can be any mammalian host, e.g., rabbit,mouse, rat, etc.) are incubated together at 37° C. This mixture is thenre-pipetted in aliquots onto a glass slide such that each aliquot has onaverage a single, antibody-producing B-cell. The antigen-specific,antibody-secreting cells are then detected through fluorescencemicroscopy. Secreted antibody is locally concentrated onto the adjacentbeads due to the bound antigen and provides localization informationbased on the strong fluorescent signal. Antibody-secreting cells areidentified via FITC detection of antibody-antigen complexes formedadjacent to the secreting cell. The single cell found in the center ofthis complex is then recovered using a micromanipulator. The cell issnap-frozen in an eppendorf PCR tube for storage at −80° C. untilantibody sequence recovery is initiated.

Example 5 Isolation of Antibody Sequences From Antigen-Specific B Cell

Antibody sequences are recovered using a combined RT-PCR based methodfrom a single isolated B-cell produced according to Example 4 or anantigenic specific B cell isolated from the clonal B cell populationobtained according to Example 2. Primers are designed to anneal inconserved and constant regions of the target immunoglobulin genes (heavyand light), such as rabbit immunoglobulin sequences, and a two-stepnested PCR recovery step is used to obtain the antibody sequence.Amplicons from each well are analyzed for recovery and size integrity.The resulting fragments are then digested with AluI to fingerprint thesequence clonality. Identical sequences display a common fragmentationpattern in their electrophoretic analysis. Significantly, this commonfragmentation pattern which proves cell clonality is generally observedeven in the wells originally plated up to 1000 cells/well. The originalheavy and light chain amplicon fragments are then restriction enzymedigested with HindIII and XhoI or HindIII and BsiWI to prepare therespective pieces of DNA for cloning. The resulting digestions are thenligated into an expression vector and transformed into bacteria forplasmid propagation and production. Colonies are selected for sequencecharacterization.

Example 6 Recombinant Production of Monoclonal Antibody of DesiredAntigen Specificity and/or Functional Properties

Correct full-length antibody sequences for each well containing a singlemonoclonal antibody is established and miniprep DNA is prepared usingQiagen solid-phase methodology. This DNA is then used to transfectmammalian cells to produce recombinant full-length antibody. Crudeantibody product is tested for antigen recognition and functionalproperties to confirm the original characteristics are found in therecombinant antibody protein. Where appropriate, large-scale transientmammalian transfections are completed, and antibody is purified throughProtein A affinity chromatography. Kd is assessed using standard methods(e.g., Biacore) as well as IC50 in a potency assay.

Example 7 Preparation of Antibodies that Bind Human IL-6

By using the antibody selection protocol described herein, one cangenerate an extensive panel of antibodies. The antibodies have highaffinity towards IL-6 (single to double digit pM Kd) and demonstratepotent antagonism of IL-6 in multiple cell-based screening systems(T1165 and HepG2). Furthermore, the collection of antibodies displaydistinct modes of antagonism toward IL-6-driven processes.

Immunization Strategy

Rabbits were immunized with huIL-6 (R&R). Immunization consisted of afirst subcutaneous (sc) injection of 100 μg in complete Freund'sadjuvant (CFA) (Sigma) followed by two boosts, two weeks apart, of 50 μgeach in incomplete Freund's adjuvant (WA) (Sigma). Animals were bled onday 55, and serum titers were determined by ELISA (antigen recognition)and by non-radioactive proliferation assay (Promega) using the T1165cell line.

Antibody Selection Titer Assessment

Antigen recognition was determined by coating Immulon 4 plates (Thermo)with 1 μg/ml of huIL-6 (50 μl/well) in phosphate buffered saline (PBS,Hyclone) overnight at 4° C. On the day of the assay, plates were washed3 times with PBS/Tween 20 (PBST tablets, Calbiochem). Plates were thenblocked with 200 μl/well of 0.5% fish skin gelatin (FSG, Sigma) in PBSfor 30 minutes at 37° C. Blocking solution was removed, and plates wereblotted. Serum samples were made (bleeds and pre-bleeds) at a startingdilution of 1:100 (all dilutions were made in FSG 50 μl/well) followedby 1:10 dilutions across the plate (column 12 was left blank forbackground control). Plates were incubated for 30 minutes at 37° C.Plates were washed 3 times with PBS/Tween 20. Goat anti-rabbit FC-HRP(Pierce) diluted 1:5000 was added to all wells (50 μl/well), and plateswere incubated for 30 minutes at 37° C. Plates were washed as describedabove. 50 μl/well of TMB-Stable stop (Fitzgerald Industries) was addedto plates, and color was allowed to develop, generally for 3 to 5minutes. The development reaction was stopped with 50 μl/well 0.5 M HCl.Plates were read at 450 nm. Optical density (OD) versus dilution wasplotted using Graph Pad Prizm software, and titers were determined.

Functional Titer Assessment

The functional activity of the samples was determined by a T1165proliferation assay. T1165 cells were routinely maintained in modifiedRPMI medium (Hyclone) supplemented with Hepes, sodium pyruvate, sodiumbicarbonate, L-glutamine, high glucose, penicillin/streptomycin, 10%heat inactivated fetal bovine serum (FBS) (all supplements fromHyclone), 2-mercaptoethanol (Sigma), and 10 ng/ml of huIL-6 (R&D). Onthe day of the assay, cell viability was determined by trypan blue(Invitrogen), and cells were seeded at a fixed density of 20,000cells/well. Prior to seeding, cells were washed twice in the mediumdescribed above without human-IL-6 (by centrifuging at 13000 rpm for 5minutes and discarding the supernatant). After the last wash, cells wereresuspended in the same medium used for washing in a volume equivalentto 50 μl/well. Cells were set aside at room temperature.

In a round-bottom, 96-well plate (Costar), serum samples were addedstarting at 1:100, followed by a 1:10 dilution across the plate (columns2 to 10) at 30 μl/well in replicates of 5 (rows B to F: dilution made inthe medium described above with no huIL-6). Column 11 was medium onlyfor IL-6 control. 30 μl/well of huIL-6 at 4× concentration of the finalEC50 (concentration previously determined) were added to all wells(huIL-6 was diluted in the medium described above). Wells were incubatedfor 1 hour at 37° C. to allow antibody binding to occur. After 1 hour,50 μl/well of antibody-antigen (Ab-Ag) complex were transferred to aflat-bottom, 96-well plate (Costar) following the plate map format laidout in the round-bottom plate. On Row G, 50 μl/well of medium were addedto all wells (columns 2 to 11) for background control. 50 μl/well of thecell suspension set aside were added to all wells (columns 2 to 11, rowsB to G). On Columns 1 and 12 and on rows A and H, 200 μl/well of mediumwas added to prevent evaporation of test wells and to minimize edgeeffect. Plates were incubated for 72 h at 37° C. in 4% CO2. At 72 h, 20μl/well of CellTiter96 (Promega) reagents was added to all test wellsper manufacturer protocol, and plates were incubated for 2 h at 37° C.At 2 h, plates were gently mixed on an orbital shaker to disperse cellsand to allow homogeneity in the test wells. Plates were read at 490 nmwavelength. Optical density (OD) versus dilution was plotted using GraphPad Prizm software, and functional titer was determined. A positiveassay control plate was conducted as described above using MAB2061 (R&DSystems) at a starting concentration of 1 μg/ml (final concentration)followed by 1:3 dilutions across the plate.

Tissue Harvesting

Once acceptable titers were established, the rabbit(s) were sacrificed.Spleen, lymph nodes, and whole blood were harvested and processed asfollows:

Spleen and lymph nodes were processed into a single cell suspension bydisassociating the tissue and pushing through sterile wire mesh at 70 μm(Fisher) with a plunger of a 20 cc syringe. Cells were collected in themodified RPMI medium described above without huIL-6, but with lowglucose. Cells were washed twice by centrifugation. After the last wash,cell density was determined by trypan blue. Cells were centrifuged at1500 rpm for 10 minutes; the supernatant was discarded. Cells wereresuspended in the appropriate volume of 10% dimethyl sulfoxide (DMSO,Sigma) in FBS (Hyclone) and dispensed at 1 ml/vial. Vials were thenstored at −70° C. for 24 h prior to being placed in a liquid nitrogen(LN2) tank for long-term storage.

Peripheral blood mononuclear cells (PBMCs) were isolated by mixing wholeblood with equal parts of the low glucose medium described above withoutFBS. 35 ml of the whole blood mixture was carefully layered onto 8 ml ofLympholyte Rabbit (Cedarlane) into a 45 ml conical tube (Corning) andcentrifuged 30 minutes at 2500 rpm at room temperature without brakes.After centrifugation, the PBMC layers were carefully removed using aglass Pasteur pipette (VWR), combined, and placed into a clean 50 mlvial. Cells were washed twice with the modified medium described aboveby centrifugation at 1500 rpm for 10 minutes at room temperature, andcell density was determined by trypan blue staining. After the lastwash, cells were resuspended in an appropriate volume of 10% DMSO/FBSmedium and frozen as described above.

B Cell Culture

On the day of setting up B cell culture, PBMC, splenocyte, or lymph nodevials were thawed for use. Vials were removed from LN2 tank and placedin a 37° C. water bath until thawed. Contents of vials were transferredinto 15 ml conical centrifuge tube (Corning) and 10 ml of modified RPMIdescribed above was slowly added to the tube. Cells were centrifuged for5 minutes at 1.5K rpm, and the supernatant was discarded. Cells wereresuspended in 10 ml of fresh media. Cell density and viability wasdetermined by trypan blue. Cells were washed again and resuspended at1E07 cells/80 ul medium. Biotinylated huIL-6 (B huIL-6) was added to thecell suspension at the final concentration of 3 ug/mL and incubated for30 minutes at 4° C. Unbound B huIL-6 was removed with two 10 ml washesof phosphate-buffered (PBF):Ca/Mg free PBS (Hyclone), 2 mMethylenediamine tetraacetic acid (EDTA), 0.5% bovine serum albumin (BSA)(Sigma-biotin free). After the second wash, cells were resuspended at1E07 cells/80 μl PBF. 20 μl of MACS® streptavidin beads (Milteni)/10E7cells were added to the cell suspension. Cells were incubated at 4° C.for 15 minutes. Cells were washed once with 2 ml of PBF/10E7 cells.After washing, the cells were resuspended at 1E08 cells/500 μl of PBFand set aside. A MACS® MS column (Milteni) was pre-rinsed with 500 ml ofPBF on a magnetic stand (Milteni). Cell suspension was applied to thecolumn through a pre-filter, and unbound fraction was collected. Thecolumn was washed with 1.5 ml of PBF buffer. The column was removed fromthe magnet stand and placed onto a clean, sterile 5 ml PolypropyleneFalcon tube. 1 ml of PBF buffer was added to the top of the column, andpositive selected cells were collected. The yield and viability ofpositive and negative cell fraction was determined by trypan bluestaining. Positive selection yielded an average of 1% of the startingcell concentration.

A pilot cell screen was established to provide information on seedinglevels for the culture. Three 10-plate groups (a total of 30 plates)were seeded at 50, 100, and 200 enriched B cells/well. In addition, eachwell contained 50K cells/well of irradiated EL-4.B5 cells (5,000 Rads)and an appropriate level of T cell supernatant (ranging from 1-5%depending on preparation) in high glucose modified RPMI medium at afinal volume of 250 μl/well. Cultures were incubated for 5 to 7 days at37° C. in 4% CO2.

Identification of Selective Antibody Secreting B Cells

Cultures were tested for antigen recognition and functional activitybetween days 5 and 7.

Antigen Recognition Screening

The ELISA format used is as described above except 50 μl of supernatantfrom the B cell cultures (BCC) wells (all 30 plates) was used as thesource of the antibody. The conditioned medium was transferred toantigen-coated plates. After positive wells were identified, thesupernatant was removed and transferred to a 96-well master plate(s).The original culture plates were then frozen by removing all thesupernatant except 40 μl/well and adding 60 μl/well of 16% DMSO in FBS.Plates were wrapped in paper towels to slow freezing and placed at −70°C.

Functional Activity Screening

Master plates were then screened for functional activity in the T1165proliferation assay as described before, except row B was media only forbackground control, row C was media+IL-6 for positive proliferationcontrol, and rows D-G and columns 2-11 were the wells from the BCC (50μl/well, single points). 40 μl of IL-6 was added to all wells except themedia row at 2.5 times the EC50 concentration determined for the assay.After 1 h incubation, the Ab/Ag complex was transferred to a tissueculture (TC) treated, 96-well, flat-bottom plate. 20 μl of cellsuspension in modified RPMI medium without huIL-6 (T1165 at 20,000cells/well) was added to all wells (100 μl final volume per well).Background was subtracted, and observed OD values were transformed into% of inhibition.

B Cell Recovery

Plates containing wells of interest were removed from −70° C., and thecells from each well were recovered with 5-200 μl washes of medium/well.The washes were pooled in a 1.5 ml sterile centrifuge tube, and cellswere pelleted for 2 minutes at 1500 rpm.

The tube was inverted, the spin repeated, and the supernatant carefullyremoved. Cells were resuspended in 100 μl/tube of medium. 100 μlbiotinylated IL-6 coated streptavidin M280 dynabeads (Invitrogen) and 16μl of goat anti-rabbit H&L IgG-FITC diluted 1:100 in medium was added tothe cell suspension.

20 μl of cell/beads/FITC suspension was removed, and 5 μl droplets wereprepared on a glass slide (Corning) previously treated with Sigmacote(Sigma), 35 to 40 droplets/slide. An impermeable barrier of parafin oil(JT Baker) was added to submerge the droplets, and the slide wasincubated for 90 minutes at 37° C., 4% CO2 in the dark.

Specific B cells that produce antibody can be identified by thefluorescent ring around them due to antibody secretion, recognition ofthe bead-associated biotinylated antigen, and subsequent detection bythe fluorescent-IgG detection reagent. Once a cell of interest wasidentified, the cell in the center of the fluorescent ring was recoveredvia a micromanipulator (Eppendorf). The single cell synthesizing andexporting the antibody was transferred into a 250 μl microcentrifugetube and placed in dry ice. After recovering all cells of interest,these were transferred to −70° C. for long-term storage.

Example 8 Yeast Cell Expression

Antibody Genes:

Genes were cloned and constructed that directed the synthesis of achimeric humanized rabbit monoclonal antibody.

Expression Vector:

The vector contains the following functional components: 1) a mutantColE1 origin of replication, which facilitates the replication of theplasmid vector in cells of the bacterium Escherichia coli; 2) abacterial Sh ble gene, which confers resistance to the antibiotic Zeocinand serves as the selectable marker for transformations of both E. coliand P. pastoris; 3) an expression cassette composed of theglyceraldehyde dehydrogenase gene (GAP gene) promoter, fused tosequences encoding the Saccharomyces cerevisiae alpha mating factor prepro secretion leader sequence, followed by sequences encoding a P.pastoris transcriptional termination signal from the P. pastoris alcoholoxidase I gene (AOX1). The Zeocin resistance marker gene provides ameans of enrichment for strains that contain multiple integrated copiesof an expression vector in a strain by selecting for transformants thatare resistant to higher levels of Zeocin.

P. pastoris Strains:

P. pastoris strains met1, lys3, ura3 and ade1 may be used. Although anytwo complementing sets of auxotrophic strains could be used for theconstruction and maintenance of diploid strains, these two strains areespecially suited for this method for two reasons. First, they grow moreslowly than diploid strains that are the result of their mating orfusion. Thus, if a small number of haploid ade1 or ura3 cells remainpresent in a culture or arise through meiosis or other mechanism, thediploid strain should outgrow them in culture.

The second is that it is easy to monitor the sexual state of thesestrains since diploid Ade+ colonies arising from their mating are anormal white or cream color, whereas cells of any strains that arehaploid ade1 mutants will form a colony with a distinct pink color. Inaddition, any strains that are haploid ura3 mutants are resistant to thedrug 5-fluoro-orotic acid (FOA) and can be sensitively identified byplating samples of a culture on minimal medium+uracil plates with FOA.On these plates, only uracil-requiring ura3 mutant (presumably haploid)strains can grow and form colonies. Thus, with haploid parent strainsmarked with ade1 and ura3, one can readily monitor the sexual state ofthe resulting antibody-producing diploid strains (haploid versusdiploid).

Methods

Construction of pGAPZ-Alpha Expression Vectors for Transcription ofLight and Heavy Chain Antibody Genes.

The humanized light and heavy chain fragments were cloned into the pGAPZexpression vectors through a PCR directed process. The recoveredhumanized constructs were subjected to amplification under standard KODpolymerase (Novagen) kit conditions ((1) 94° C., 2 minutes; (2) 94° C.,30 seconds (3) 55° C., 30 seconds; (4) 72° C., 30 seconds-cyclingthrough steps 2-4 for 35 times; (5) 72° C. 2 minutes) employing thefollowing primers (1) light chain forward

AGCGCT TATTCCGCTATCCAGATGACCCAGTCthe AfeI site is single underlined. The end of the HSA signal sequenceis double underlined, followed by the sequence for the mature variablelight chain (not underlined); the reverse

CGTACGTTTGATTTCCACCTTG.

Variable light chain reverse primer. BsiWI site is underlined, followedby the reverse complement for the 3′ end of the variable light chain.Upon restriction enzyme digest with AfeI and BsiWI this enable insertionin-frame with the pGAPZ vector using the human HAS leader sequence inframe with the human kapp light chain constant region for export. (2) Asimilar strategy is performed for the heavy chain. The forward primeremployed is

AGCGCT TATTCCGAGGTGCAGCTGGTGGAGTC.The AfeI site is single underlined. The end of the HSA signal sequenceis double underlined, followed by the sequence for the mature variableheavy chain (not underlined). The reverse heavy chain primer is

CTCGAGACGGTGACGAGGGT.The XhoI site is underlined, followed by the reverse complement for the3′ end of the variable heavy chain. This enables cloning of the heavychain in-frame with IgG-γ1 CH1-CH2-CH3 region previous inserted withinpGAPZ using a comparable directional cloning strategy.

Transformation of Expression Vectors into Haploid Ade1 Ura3, Met1 andLys3 Host Strains of P. pastoris.

All methods used for transformation of haploid P. pastoris strains andgenetic manipulation of the P. pastoris sexual cycle are as described inHiggins, D. R., and Cregg, J. M., Eds. 1998. Pichia Protocols. Methodsin Molecular Biology. Humana Press, Totowa, N.J.

Prior to transformation, each expression vector is linearized within theGAP promoter sequences with AvrII to direct the integration of thevectors into the GAP promoter locus of the P. pastoris genome. Samplesof each vector are then individually transformed into electrocompetentcultures of the ade1, ura3, met1 and lys3 strains by electroporation andsuccessful transformants are selected on YPD Zeocin plates by theirresistance to this antibiotic. Resulting colonies are selected, streakedfor single colonies on YPD Zeocin plates and then examined for thepresence of the antibody gene insert by a PCR assay on genomic DNAextracted from each strain for the proper antibody gene insert and/or bythe ability of each strain to synthesize an antibody chain by a colonylift/immunoblot method (Wung et al. Biotechniques 21 808-812 (1996).Haploid ade1, met1 and lys3 strains expressing one of the three heavychain constructs are collected for diploid constructions along withhaploid ura3 strain expressing light chain gene. The haploid expressingheavy chain genes are mated with the appropriate light chain haploidura3 to generate diploid secreting protein.

Mating of haploid strains synthesizing a single antibody chain andselection of diploid derivatives synthesizing tetrameric functionalantibodies. To mate P. pastoris haploid strains, each ade1 (or met1 orlys3) heavy chain producing strain to be crossed is streaked across arich YPD plate and the ura3 light chain producing strain is streakedacross a second YPD plate (˜10 streaks per plate). After one or two daysincubation at 30° C., cells from one plate containing heavy chainstrains and one plate containing ura3 light chain strains aretransferred to a sterile velvet cloth on a replica-plating block in across hatched pattern so that each heavy chain strain contain a patch ofcells mixed with each light chain strain. The cross-streaked replicaplated cells are then transferred to a mating plate and incubated at 25°C. to stimulate the initiation of mating between strains. After twodays, the cells on the mating plates are transferred again to a sterilevelvet on a replica-plating block and then transferred to minimal mediumplates. These plates are incubated at 30° C. for three days to allow forthe selective growth of colonies of prototrophic diploid strains.Colonies that arose are picked and streaked onto a second minimal mediumplate to single colony isolate and purify each diploid strain. Theresulting diploid cell lines are then examined for antibody production.

Putative diploid strains are tested to demonstrate that they are diploidand contain both expression vectors for antibody production. Fordiploidy, samples of a strain are spread on mating plates to stimulatethem to go through meiosis and form spores. Haploid spore products arecollected and tested for phenotype. If a significant percentage of theresulting spore products are single or double auxotrophs it may beconcluded that the original strain must have been diploid. Diploidstrains are examined for the presence of both antibody genes byextracting genomic DNA from each and utilizing this DNA in PCR reactionsspecific for each gene.

Fusion of haploid strains synthesizing a single antibody chain andselection of diploid derivatives synthesizing tetrameric functionalantibodies. As an alternative to the mating procedure described above,individual cultures of single-chain antibody producing haploid ade1 andura3 strains are spheroplasted and their resulting spheroplasts fusedusing polyethylene glycol/CaCl₂. The fused haploid strains are thenembedded in agar containing 1 M sorbitol and minimal medium to allowdiploid strains to regenerate their cell wall and grow into visiblecolonies. Resulting colonies are picked from the agar, streaked onto aminimal medium plate, and the plates are incubated for two days at 30°C. to generate colonies from single cells of diploid cell lines. Theresulting putative diploid cell lines are then examined for diploidy andantibody production as described above.

Purification and analysis of antibodies. A diploid strain for theproduction of full length antibody is derived through the mating of met1light chain and lys3 heavy chain using the methods described above.Culture media from shake-flask or fermenter cultures of diploid P.pastoris expression strains are collected and examined for the presenceof antibody protein via SDS-PAGE and immunoblotting using antibodiesdirected against heavy and light chains of human IgG, or specificallyagainst the heavy chain of IgG.

To purify the yeast secreted antibodies, clarified media from antibodyproducing cultures are passed through a protein A column and afterwashing with 20 mM sodium phosphate, pH 7.0, binding buffer, protein Abound protein is eluted using 0.1 M glycine HCl buffer, pH 3.0.Fractions containing the most total protein are examined by Coomasieblue strained SDS-PAGE and immunoblotting for antibody protein. Antibodyis characterized using the ELISA described above for IL-6 recognition.

Assay for Antibody Activity.

The recombinant yeast-derived humanized antibody is evaluated forfunctional activity through the IL-6 driven T1165 cell proliferationassay and IL-6 stimulated HepG2 haptoglobin assay described above.

Example 9 Acute Phase Response Neutralization by IntravenousAdministration of Anti-IL-6 Antibody Ab1

Human IL-6 can provoke an acute phase response in rats, and one of themajor acute phase proteins that is stimulated in the rat is α-2macroglobulin (A2M). A study was designed to assess the dose of antibodyAb1 required to ablate the A2M response to a single s.c. injection of100 μg of human IL-6 given one hour after different doses (0.03, 0.1,0.3, 1, and 3 mg/kg) of antibody Ab1 administered intravenously (n=10rats/dose level) or polyclonal human IgG1 as the control (n=10 rats).Plasma was recovered and the A2M was quantitated via a commercialsandwich ELISA kit (ICL Inc., Newberg or; cat. no.-E-25A2M). Theendpoint was the difference in the plasma concentration of A2M at the 24hour time point (post-Ab1). The results are presented in FIG. 4.

The ID50 for antibody Ab1 was 0.1 mg/kg with complete suppression of theA2M response at the 0.3 mg/kg. This firmly establishes in vivoneutralization of human IL-6 can be accomplished by antibody Ab1.

Example 10 RXF393 Cachexia Model Study 1

Introduction

The human renal cell cancer cell line, RXF393 produces profound weightloss when transplanted into athymic nude mice. Weight loss begins aroundday 15 after transplantation with 80% of all animals losing at least 30%of their total body weight by day 18-20 after transplantation. RXF393secretes human IL-6 and the plasma concentration of human IL-6 in theseanimals is very high at around 10 ng/ml. Human IL-6 can bind murinesoluble IL-6 receptor and activate IL-6 responses in the mouse. HumanIL-6 is approximately 10 times less potent than murine IL-6 atactivating IL-6 responses in the mouse. The objectives of this studywere to determine the effect of antibody Ab1, on survival, body weight,serum amyloid A protein, and hematology parameters in athymic nude micetransplanted with the human renal cell cancer cell line, RXF393.

Methods

Eighty, 6 week old, male athymic nude mice were implanted with RXF393tumor fragments (30-40 mg) subcutaneously in the right flank. Animalswere then divided into eight groups of ten mice. Three groups were giveneither antibody Ab1 at 3 mg/kg, 10 mg/kg, or 30 mg/kg intravenouslyweekly on day 1, day 8, day 15 and day 22 after transplantation(progression groups). Another three groups were given either antibodyAb1 at 3 mg/kg, or 10 mg/kg, or 30 mg/kg intravenously weekly on day 8,day 15 and day 22 after transplantation (regression groups). Finally,one control group was given polyclonal human IgG 30 mg/kg and a secondcontrol group was given phosphate buffered saline intravenously weeklyon day 1, day 8, day 15 and day 22 after transplantation.

Animals were euthanized at either day 28, when the tumor reached 4,000mm³ or if they became debilitated (>30% loss of body weight). Animalswere weighed on days 1, 6 and then daily from days 9 to 28 aftertransplantation. Mean Percent Body Weight (MPBW) was used as the primaryparameter to monitor weight loss during the study. It was calculated asfollows: (Body Weight−Tumor Weight)/Baseline Body Weight×100. Tumorweight was measured on days 1, 6, 9, 12, 15, 18, 22, 25 and 28 aftertransplantation. Blood was taken under anesthesia from five mice in eachgroup on days 5 and 13 and all ten mice in each group when euthanized(day 28 in most cases). Blood was analyzed for hematology and serumamyloid A protein (SAA) concentration. An additional group of 10non-tumor bearing 6 week old, athymic nude male mice had blood samplestaken for hematology and SAA concentration estimation to act as abaseline set of values.

Results—Survival

No animals were euthanized or died in any of the antibody Ab1 groupsprior to the study termination date of day 28. In the two controlgroups, 15 animals (7/9 in the polyclonal human IgG group and 8/10 inthe phosphate buffered saline group) were found dead or were euthanizedbecause they were very debilitated (>30% loss of body weight). Mediansurvival time in both control groups was 20 days.

The survival curves for the two control groups and the antibody Ab1progression (dosed from day 1 of the study) groups are presented in FIG.5.

The survival curves for the two control groups and the antibody Ab1regression (dosed from day 8 of the study) groups are presented in FIG.6.

There was a statistically significant difference between the survivalcurves for the polyclonal human IgG (p=0.0038) and phosphate bufferedsaline (p=0.0003) control groups and the survival curve for the sixantibody Ab1 groups. There was no statistically significant differencebetween the two control groups (p=0.97).

Results—Plasma Serum Amyloid A

The mean (±SEM) plasma serum amyloid A concentration versus time for thetwo control groups and the antibody Ab1 progression (dosed from day 1 ofthe study) and regression (dosed from day 8 of the study) groups arepresented in Table 1.

TABLE 1 Mean Plasma SAA - antibody Ab1, all groups versus control groupsMean Plasma Mean Plasma Mean Plasma SAA ± SEM SAA ± SEM SAA ± SEM Day 5Day 13 Terminal Bleed (μg/ml) (μg/ml) (μg/ml) Polyclonal IgG iv 675 ±240 3198 ± 628 13371 ± 2413 weekly from day 1 (n = 5) (n = 4) (n = 4)PBS iv weekly 355 ± 207  4844 ± 1126 15826 ± 802  from day 1 (n = 5) (n= 5) (n = 3) Ab1 30 mg/kg iv 246 ± 100 2979 ± 170  841 ± 469 weekly fromday 1 (n = 5) (n = 5)  (n = 10) Ab1 10 mg/kg iv 3629 ± 624  3096 ± 690 996 ± 348 weekly from day 1 (n = 5) (n = 5)  (n = 10) Ab1 3 mg/kg iv106 ± 9  1623 ± 595 435 ± 70 weekly from day 1 (n = 5) (n = 4) (n = 9)Ab1 30 mg/kg iv 375 ± 177 1492 ± 418 498 ± 83 weekly from day 8 (n = 5)(n = 4) (n = 9) Ab1 10 mg/kg iv 487 ± 170 1403 ± 187 396 ± 58 weeklyfrom day 8 (n = 5) (n = 5)  (n = 10) Ab1 3 mg/kg iv 1255 ± 516   466 ±157  685 ± 350 weekly from day 8 (n = 5) (n = 5) (n = 5)

SAA is up-regulated via the stimulation of hIL-6 and this response isdirectly correlated with circulating levels of hIL-6 derived from theimplanted tumor. The surrogate marker provides an indirect readout foractive hIL-6. Thus in the two treatment groups described above there aresignificantly decreased levels of SAA due to the neutralization oftumor-derived hIL-6. This further supports the contention that antibodyAb1 displays in vivo efficacy.

Example 11 RXF393 Cachexia Model Study 2

Introduction

A second study was performed in the RXF-393 cachexia model wheretreatment with antibody Ab1 was started at a later stage (days 10 and 13post-transplantation) and with a more prolonged treatment phase (out to49 days post transplantation). The dosing interval with antibody Ab1 wasshortened to 3 days from 7 and also daily food consumption was measured.There was also an attempt to standardize the tumor sizes at the time ofinitiating dosing with antibody Ab1.

Methods

Eighty, 6 week old, male athymic nude mice were implanted with RXF393tumor fragments (30-40 mg) subcutaneously in the right flank. 20 micewere selected whose tumors had reached between 270-320 mg in size anddivided into two groups. One group received antibody Ab1 at 10 mg/kgi.v. every three days and the other group received polyclonal human IgG10 mg/kg every 3 days from that time-point (day 10 aftertransplantation). Another 20 mice were selected when their tumor sizehad reached 400-527 mg in size and divided into two groups. One groupreceived antibody Ab1 at 10 mg/kg i.v. every three days and the othergroup received polyclonal human IgG 10 mg/kg every 3 days from thattime-point (day 13 after transplantation). The remaining 40 mice took nofurther part in the study and were euthanized at either day 49, when thetumor reached 4,000 mm³ or if they became very debilitated (>30% loss ofbody weight).

Animals were weighed every 3-4 days from day 1 to day 49 aftertransplantation. Mean Percent Body Weight (MPBW) was used as the primaryparameter to monitor weight loss during the study. It was calculated asfollows: ((Body Weight−Tumor Weight)/Baseline Body Weight)×100. Tumorweight was measured every 3-4 days from day 5 to day 49 aftertransplantation. Food consumption was measured (amount consumed in 24hours by weight (g) by each treatment group) every day from day 10 forthe 270-320 mg tumor groups and day 13 for the 400-527 mg tumor groups.

Results—Survival

The survival curves for antibody Ab1 at 10 mg/kg i.v. every three days(270-320 mg tumor size) and for the polyclonal human IgG 10 mg/kg i.v.every three days (270-320 mg tumor size) are presented in FIG. 7.

Median survival for the antibody Ab1 at 10 mg/kg i.v. every three days(270-320 mg tumor size) was 46 days and for the polyclonal human IgG at10 mg/kg i.v. every three days (270-320 mg tumor size) was 32.5 days(p=0.0071).

The survival curves for the antibody Ab1 at 10 mg/kg i.v. every threedays (400-527 mg tumor size) and for the polyclonal human IgG at 10mg/kg i.v. every three days (400-527 mg tumor size) are presented inFIG. 8. Median survival for the antibody Ab1 at 10 mg/kg i.v. everythree days (400-527 mg tumor size) was 46.5 days and for the polyclonalhuman IgG at 10 mg/kg i.v. every three days (400-527 mg tumor size) was27 days (p=0.0481).

Example 12 Multi-Dose Pharmacokinetic Evaluation of Antibody Ab1 inNon-Human Primates

Antibody Ab1 was dosed in a single bolus infusion to a single male andsingle female cynomologus monkey in phosphate buffered saline. Plasmasamples were removed at fixed time intervals and the level of antibodyAb1 was quantitated through of the use of an antigen capture ELISAassay. Biotinylated IL-6 (50 μl of 3 μg/mL) was captured on Streptavidincoated 96 well microtiter plates. The plates were washed and blockedwith 0.5% Fish skin gelatin. Appropriately diluted plasma samples wereadded and incubated for 1 hour at room temperature. The supernatantsremoved and an anti-hFc-HRP conjugated secondary antibody applied andleft at room temperature.

The plates were then aspirated and TMB added to visualize the amount ofantibody. The specific levels were then determined through the use of astandard curve. A second dose of antibody Ab1 was administered at day 35to the same two cynomologus monkeys and the experiment replicated usingan identical sampling plan. The resulting concentrations are then plotvs. time as show in FIG. 9.

This humanized full length aglycosylated antibody expressed and purifiedPichia pastoris displays comparable characteristics to mammalianexpressed protein. In addition, multiple doses of this product displayreproducible half-lives inferring that this production platform does notgenerate products that display enhanced immunogenicity.

Example 13 Octet Mechanistic Characterization of Antibody Proteins

IL-6 signaling is dependent upon interactions between IL-6 and tworeceptors, IL-6R1 (CD126) and GP130 (IL-6 signal transducer). Todetermine the antibody mechanism of action, mechanistic studies wereperformed using bio-layer interferometry with an Octet QK instrument(ForteBio; Menlo Park, Calif.). Studies were performed in two differentconfigurations. In the first orientation, biotinylated IL-6 (R&D systemspart number 206-IL-001MG/CF, biotinylated using Pierce EZ-linksulfo-NHS-LC-LC-biotin product number 21338 according to manufacturer'sprotocols) was initially bound to a streptavidin coated biosensor(ForteBio part number 18-5006). Binding is monitored as an increase insignal.

The IL-6 bound to the sensor was then incubated either with the antibodyin question or diluent solution alone. The sensor was then incubatedwith soluble IL-6R1 (R&D systems product number 227-SR-025/CF) molecule.If the IL-6R1 molecule failed to bind, the antibody was deemed to blockIL-6/IL-6R1 interactions. These complexes were incubated with GP130 (R&Dsystems 228-GP-010/CF) in the presence of IL-6R1 for stability purposes.If GP130 did not bind, it was concluded that the antibody blocked GP130interactions with IL-6.

In the second orientation, the antibody was bound to a biosensor coatedwith an anti-human IgG1 Fc-specific reagent (ForteBio part number18-5001). The IL-6 was bound to the immobilized antibody and the sensorwas incubated with IL-6R1. If the IL-6R1 did not interact with the IL-6,then it was concluded that the IL-6 binding antibody blocked IL-6/IL-6R1interactions. In those situations where antibody/IL-6/IL-6R1 wasobserved, the complex was incubated with GP130 in the presence ofIL-6R1. If GP130 did not interact, then it was concluded that theantibody blocked IL-6/GP130 interactions. All studies were performed ina 200 μL final volume, at 30 C and 1000 rpms. For these studies, allproteins were diluted using ForteBio's sample diluent buffer (partnumber 18-5028).

Results are presented in FIGS. 10A-E and 11.

Example 14 Peptide Mapping

In order to determine the epitope recognized by Ab1 on human IL-6, theantibody was employed in a western-blot based assay. The form of humanIL-6 utilized in this example had a sequence of 183 amino acids inlength (shown below). A 57-member library of overlapping 15 amino acidpeptides encompassing this sequence was commercially synthesized andcovalently bound to a PepSpots nitrocellulose membrane (JPT Peptidetechnologies, Berlin, Germany). The sequences of the overlapping 15amino acid peptides is shown in FIG. 12. Blots were prepared and probedaccording to the manufacturer's recommendations.

Briefly, blots were pre-wet in methanol, rinsed in PBS, and blocked forover 2 hours in 10% non-fat milk in PBS/0.05% Tween (Blocking Solution).The Ab1 antibody was used at 1 mg/ml final dilution, and theHRP-conjugated Mouse Anti-Human-Kappa secondary antibody (SouthernBioTech #9220-05) was used at a 1:5000 dilution. Antibodydilutions/incubations were performed in blocking solution. Blots weredeveloped using Amersham ECL advance reagents (GE# RPN2135) andchemiluminescent signal documented using a CCD camera (AlphaInnotec).The results of the blots is shown in FIGS. 13 and 14.

The sequence of the form of human IL-6 utilized to generate peptidelibrary is set forth:

(SEQ ID NO: 1) VPPGEDSKDVAAPHRQPLTSSERIDKQIRYILDGISALRKETCNKSNMCESSKEALAENNLNLPKMAEKDGCFQSGFNEETCLVKIITGLLEFEVYLEYLQNRFESSEEQARAVQMSTKVLIQFLQKKAKNLDAITTPDPTTNASLLTKLQAQNQWLQDMTTHLILRSFKEFLQSSLRALRQM.

What is claimed is:
 1. An anti-human IL-6 antibody or anti-human IL-6antibody fragment which comprises a variable light chain comprising theamino acid sequence of SEQ ID NO: 709, and a variable heavy chaincomprising the amino acid sequence of SEQ ID NO:
 657. 2. An anti-humanIL-6 antibody or anti-human IL-6 antibody fragment which comprises avariable light chain comprising the amino acid sequence of SEQ ID NO:709 and a variable heavy chain comprising the amino acid sequence of SEQID NO:
 656. 3. An anti-human IL-6 antibody or anti-human IL-6 antibodyfragment of claim 1, which comprises a variable light chain comprisingthe amino acid sequence of SEQ ID NO: 702 and a variable heavy chaincomprising the amino acid sequence of SEQ ID NO:
 704. 4. Apharmaceutical composition comprising an anti-human IL-6 antibody oranti-human IL-6 antibody fragment according to claim 3 and a carrier. 5.A pharmaceutical composition comprising an anti-human IL-6 antibody oranti-human IL-6 antibody fragment according to claim 1 and a carrier. 6.The anti-human IL-6 antibody or anti-human IL-6 antibody fragment ofclaim 1 or 2, which comprises a light chain constant region comprisingthe amino acid sequence of SEQ ID NO:
 586. 7. The anti-human IL-6antibody or anti-human IL-6 antibody fragment of claim 1 or 2, whichcomprises a heavy chain constant region comprising the amino acidsequence of SEQ ID NO:
 588. 8. The anti-human IL-6 antibody oranti-human IL-6 antibody fragment of claim 1 or 2 which is a singlechain antibody.
 9. The anti-human IL-6 antibody or anti-human IL-6antibody fragment of claim 1 or 2, which contains human constant regionsselected from the group consisting of IgG1, IgG2, IgG3, IgG4, IgG5,IgG6, IgG7, IgG8, IgG9, IgG10, IgG11, IgG12, IgG13, IgG14, IgG15, IgG16,IgG17, IgG18 and IgG19 constant regions.
 10. The anti-human IL-6antibody or anti-human IL-6 antibody fragment of claim 1 or 2, whichcontains human IgG1 constant regions.
 11. A pharmaceutical compositioncomprising an anti-human IL-6 antibody or anti-human IL-6 antibodyfragment according to claim 2 and a carrier.